SESSION III. HEPATIC METABOLISM OF ORAL CONTRACEPTIVE STEROIDS Chairman: M. Orme
Interactions with oral contraceptives Kenneth Fotherby, PhD London, England The interaction of a range of different factors with the pharmacologic activity of oral contraceptives is reviewed. Pharmacokinetic interactions with oral contraceptives may occur (1) during absorption and extrahepatic circulation, (2) by interfering with protein binding, and (3) during hepatic metabolism. The hepatic mixed function oxidase system, which is mainly responsible for the metabolism of oral contraceptives, is affected by several different factors and is easily induced. Nutrition affects the activity of many drugs, but information regarding oral contraceptives is meager. Both pharmacokinetic and pharmacodynamic interactions, which may be synergistic or antagonistic, between the estrogen and gestagen components of oral contraceptives, are important, but there is no correlation between the rate of metabolism of the two components. Evidence suggests that some anticonvulsant, antibiotic, and antibacterial drugs may reduce the efficacy of oral contraceptives. Instances of interactions of other therapeutic agents are reported infrequently. The incidence of serious interactions is low and does not appear to have been reduced with low-dose oral contraceptives, probably because of large intersubject variability in the pharmacokinetics of oral contraceptives. (AM J OBSTET GVNECOL 1990;163:2153-9.)
Key words: Drug interactions, oral contraceptives, pharmacokinetics, absorption, protein binding, metabolism Considering (1) the wide variety of drugs available, (2) the large proportion of the population consuming both prescribed and over-the-counter drugs, (3) that nutritional factors may affect drug action, and (4) that many drugs have similar metabolic pathways, it is perhaps surprising that drug interactions are not more common than they appear to be. This article is concerned only with the effects of other agents on the biologic activity of contraceptive steroids, and will not examine the changes in drug activity that may be encountered in women using oral contraceptives (OCs). As far as contraceptive steroids are concerned, a clinically important decrease in their efficacy because of interaction with other drugs appears to occur in a very small minority of women «5%), and the possible reasons why the incidence is so low are considered later. This article examines only the possible loci in the metabolism of contraceptive steroids in which other drugs and nutrients might interact. A detailed listing of all the drugs likely to interact with the contraceptive steroids will not be provided, since many excellent accounts of this area are available. 1-4 The interaction of drugs and nutrients with OCs may interfere with their pharmacokinetic behavior, phar-
From the Department of Steroid Biochemistry, Royal Postgraduate Medical School, Hammersmith Hospital. Reprints are not available.
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macodynamic actions, or both. In addition, with combined OCs the interaction of the estrogen and gestagen components is of great importance. Pharmacokinetic interactions
The three main areas in which pharmacokinetic interactions may occur between contraceptive steroids and other drugs are (1) absorption, (2) serum protein binding, and (3) hepatic metabolism. Absorption. There are two mechanisms by which drugs may interact with the absorption of contraceptive steroids: by affecting the absorptive process itself or by affecting the intestinal flora. Absorption of steroids may be impaired when the rate of which they pass through the gastrointestinal tract is markedly increased because of increased intestinal motility; for example, in subjects either using laxatives or with severe or prolonged diarrhea. Ethinyl estradiol (EE) and some gestagens, such as norethisterone (NET), undergo extensive (40% to 60%) firstpass metabolism, much of which occurs in the intestinal wall. Absorption appears to occur mainly in the upper part of the intestine, since the bioavailability of EE and levonorgestrel (LNG) is not decreased by ileostomy or after jejunoileal bypass. Phase 1 metabolism of steroids can be demonstrated with intestinal tissue in vitro, and intestinal tissue contains cytochrome P-450, but under normal in vitro conditions, phase 1 metabolism by the intestine appears to be unimportant. However, the ex-
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tent to which such metabolism is increased after the administration of enzyme-inducing drugs has not been investigated. Specific effects on EE, which undergoes sulfation in the intestinal mucosa, may occur with certain drugs. Since the amount of available sulfate appears to be limited, administration in high doses of other drugs that are sulfated during absorption, such as vitamin C and paracetamol, leads to competition, less EE is sulfated, and its bioavailability is improved. Conversely, when the competing drug is stopped, more sulfation of EE occurs and its bioavailability is reduced. Contraceptive steroids also undergo an enterohepatic circulation, and this is particularly important for EE. The steroids conjugated in the liver are secreted into the intestine by way of bile and are hydrolyzed by the gut flora. If these are inhibited by the administration of antibiotics, hydrolysis of the cOrUugates is markedly reduced, which leads to reduced reabsorption of the steroids and an increase in the fecal excretion. The effects on the gestagens are clinically less important, since they are rapidly metabolized to biologically inactive products by the liver, mainly by reduction, and to a lesser extent by hydroxylation before conjugation and secretion in the bile. Metabolism of EE in the liver involves hydroxylation at various positions, and in subjects who are poor hydroxylators, more EE is available for conjugation and the extrahepatic circulation. In these subjects interference with the extrahepatic circulation produced by the administration of antibiotics may lead to markedly lower serum EE concentrations. Although the effect of some antibiotics on the gut flora provides one mechanism by which the bioavailability of contraceptive steroids, particularly EE, may be decreased, whether this is the major factor involved in the few clinically important interactions that occur remains to be conclusively demonstrated. Binding to serum proteins. The contraceptive steroids are highly bound (>95%) in blood and thus are susceptible to factors that may produce only slight modifications of the binding. Thus an insignificant 2% decrease in the amount bound could lead to a significant 50% increase in the unbound fraction on which the biologic activity of the steroids depends. EE binds only to albumin, and although interaction between drugs in respect to albumin has been demonstrated, no interaction between contraceptive steroids and this protein appears to have been reported. However, the gestagens bind both to albumin and sex hormone-binding globulin (SHBG), the extent and tightness of the binding to SHBG depending on their structure, and there is a complex equilibrium between the different fractions. Serum SHBG levels can be increased by the administration of estrogens and several other drugs. The in-
December 1990 Am J Obstet Gynecol
crease in SHBG may lead to an increase in the SHBG bound fraction, mainly at the expense of the albumin bound, from which dissociation occurs readily. Because contraceptive steroids are administered on a continuing basis, their serum concentrations will increase until a steady state is reached and a fresh equilibrium is formed among the different fractions; at this point the proportion unbound may be decreased, but the concentration of unbound may be unchanged. Therefore although there may be marked changes in the relative binding, these changes are unlikely to influence the efficacy of contraceptive steroids. These interactions between estrogen, gestagens, and SHBG are considered in more detail in a recent article.' Hepatic metabolism. The most important locus of drug interaction appears to be the mixed function oxidase system of the liver endoplasmic reticulum. This system occurs in several other tissues, but for most drugs the liver is the major site. The enzyme system has a low specificity, performing a number of different metabolic transformations, all of which involve cytochrome P-450, cytochrome C reductase, a flavoprotein, and reduced nicotinamide adenine dinucleotide phosphate, and its activity is stimulated by many drugs. As a result, not only is the administered drug metabolized more quickly, with a decrease in its blood concentration and biologic activity, but so are several other drugs that may be administered concurrently. There are a number of distinct P-450s," each of which may be under separate genetic control, and this may account for some of the interindividual variability in the rate of drug metabolism. The low specificity of the enzyme system as a whole enables it to metabolize a large number of different drugs and endogenous compounds, including the gonadal and adrenocortical steroids. Each of the distinct cytochrome P-450s may exert its main activity toward groups of substrates, with a variable amount of overlap between groups, and this accounts for the competitive inhibition that can occur among different substrates. In addition to genetic factors, the rate of drug metabolism is influenced by a large number of environmental factors, diet, alcohol use, smoking, medication, and pathologic conditions, and all these various factors may affect the mixed function oxidase activity of the liver. Despite the low or overlapping specificity of the mixed function oxidase system, there is often marked selectively, both positional and stereochemically, in the metabolism of the substrate. With the steroids, which can be oxidized at several different sites in the molecule, the resulting hydroxylations occur to a variable extent and they can be inhibited differently by various factors. Again this suggests that multiple forms of cytochrome P-450 are present with different specifications. The relative activities of the different cytochrome P-450s ap-
Volume 163 Number 6, Part 2
pear to vary among subjects, and if so, it is important in accounting for much of the interindividual variation in drug metabolism. The increase in the activity of the mixed function oxidase system produced by the administration of an inducing drug leads to an increase in the rate of metabolism of any contraceptive steroid the subject may use, so that the half-life of elimination of the steroid, and consequently its serum concentration and biologic effect, are decreased. Conversely, the administration of contraceptive steroids usually has an inhibitory effect on the metabolism of other drugs, which leads to an increase in their pharmacologic activity.3 The mechanism of this inhibitory effect in humans is not entirely clear. In animals, mainly the rat, the administration of steroids containing the ethinyl group, which encompasses most of the contraceptive steroids currently used, appears to inactivate cytochrome P-450, with a consequent decrease in the drug-metabolizing capacity of the liver. It was first demonstrated in humans in 1969 that EE may be metabolized by way of oxidation of the ethinyl group, which results in the formation of o-homosteroids and small amounts of estrone and estradiol. The oxidation of the ethinyl group is a complex reaction involving the production of numerous reactive intermediates. It appears that one or more of these metabolites interacts with, and leads to the destruction of, the heme group of cytochrome P450, with a consequent loss of its drug-metabolizing activity both toward the steroid and other administered drugs metabolized by the mixed function oxidase system. 7.9 As a result, the pharmacologic effect of such drugs is increased. There is evidence of the in vitro formation of o-homosteroids from ethinyl steroids in the rabbit and monkey, in addition to humans. 1O Several other chemical structures, in addition to the ethinyl group, may have a similar destructive effect on cytochrome P-450. II An increased excretion of porphyrin precursors and coproporphyrin was reported to occur in women taking OCS,I2 which could indicate an increased turnover of cytochrome P-450 heme. One reactive intermediate in the oxidation of the ethinyl group is an epoxide, and these compounds may also be formed by oxidation at the carbon 4-5 double bond of the steroids." Interestingly, the epoxides of norethisterone (NET) and levonorgestrel (LNG) may show differences in their biologic activities. I4 However, these epoxides do not appear to be implicated in heme destruction, so that the effect produced by oxidation of the ethinyl group must be from some other reactive intermediate. Many questions still remain to be answered in respect to the inhibition of cytochrome P450. Destruction appears to apply only to the heme part, which could readily be resynthesized; the apoprotein appears to be unaffected. So far heme de-
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struction has been demonstrated only in the rat and in in vitro studies; whether it occurs and to what extent in humans remains to be determined. In women metabolism of the ethinyl group is only a minor pathway for EE and probably even less so for NET and LNG. Destruction of cytochrome P-450 by metabolites of the ethinyl steroids provides one mechanism by which contraceptive steroids may impair the metabolism of coadministered drugs. Whether the concentration of the reactive intermediates attains a level sufficient to impair the cytochrome P-450 system with short-term administration of contraceptive steroids seems unlikely, although drug interactions may occur under these conditions. However, with long-term use of steroidal contraception, the situation may be different. A decreased concentration of cytochrome P-450 was found in liver microsomes from monkeys that had received contraception steroids for at least 10 years,I5 although the factors responsible need to be identified. Even if heme destruction by contraceptive steroids with a consequent reduction in the drug-metabolizing capacity of the liver occurs in humans, it does not rule out the possibility that other mechanisms may exist and may be more important for the steroidal inhibition of drug metabolism. Even small doses of gestagens administered without estrogen may inhibit drug metabolism. I6 Conversely, Mills et al. I7 reported that the clearance of NET increased in women treated with 2.5 mg of NET daily. Any of these mechanisms provides a means by which contraceptive steroids are able to inhibit their metabolism, with a consequent increase over time in the pharmacologic effects. Nutritional effects
In considering nutritional effects, it is necessary to distinguish between effects related to the quantity of the diet and those related to its quality. The former will depend on whether caloric intake in relation to energy expenditure is very low, leading to a low body mass index (BMI) and in extreme cases to anorexia nervosa, or very high, leading a high BMI and obesity. The quality will depend on the composition of a diet that is satisfactory in relation to caloric requirements. The influence of diet and nutrition on the clinical pharmacokinetics of drugs in general has been reviewed. IS Food intake affects absorption and bioavailability of several drugs I9. 2o but little information is available regarding contraceptive steroids. Absorption of some lipid-soluble drugs is increased by a high-fat diet, but no investigations have been performed to determine whether this also applies to lipidsoluble contraceptive steroids. The pharmacokinetics of many drugs may be altered in obese subjects, particularly lipid-soluble drugs such as steroids, for which the apparent volume of distribution may be greatly
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increased. However, in a preliminary comparison of two gestagens in healthy subjects, medroxyprogesterone acetate and NET enanthate given by intramuscular injection so that the effects of intestinal absorption were eliminated, differences in the pharmacokinetics between obese (BMI > 28) and thin (BMI < 20) subjects were minimal. 21 The elimination half-life of NET was significantly lower (mean, 5.9 hours) in a group of Indian women in a low socioeconomic group with poor nutritional status compared with that (13.4 hours) of well-nourished women in a high socioeconomic group.22 Similar findings have also been reported for LNG. 23 The extent to which these findings can be ascribed to low serum protein levels in the former group remains to be determined. In a preliminary study of estradiol, and presumably the same situation holds for EE, 2-hydroxylation was increased and 16cx-hydroxylation was decreased in anorexic subjects, whereas the reverse was observed in obese subjects. 24 High-protein diets appear to stimulate the activity of the hepatic drug-oxidizing system, with a consequent increased rate of metabolism of many drugs. The 2-hydrozylation of estradiol is enhanced but apparently without any concomitant change in 16cxhydrozylation,18 and the activity of the hepatic 5cxreductase is decreased. High-carbohydrate diets decrease 2-hydrozylation. A low-fat diet was also reported to increase 2-hydroxylation of estradiol and to decrease 16cx-hydroxylation!5 although this diet was also probably a high-protein one. Diet also has a marked influence on endogenously secreted androgens in humans,26 and by analogy might be expected to affect the metabolism of gestagens. Certain specific nutrients, such as charcoal-broiled beef and cruciferous vegetables, stimulate the hepatic mixed function oxidase system. Whether metabolism of contraceptive steroids differs between vegetarians and nonvegetarians is still controversial. Vegetarian diets tend to contain less fat and more fiber than nonvegetarian diets, and these differences appear to influence the metabolism of endogenous estrogens, which leads to a decrease in plasma estradiol concentrations. 27 This decrease might be partly caused by a decrease in the enterohepatic circulation. However, there were no significant differences in the pharmacokinetics of NET between lactovegetarian and nonvegetarian women. 28 One determinant of whether there are differences in drug metabolism between vegetarians and non vegetarians appears to be the amount of protein in the diet. In many of the situations discussed above, changes occur in serum SHBG concentrations, and while these changes will not affect EE, which does not bind to SHBG, they will affect the unbound biologically active fraction of the gestagens. Serum SHBG shows an in-
December 1990 Am J Obstet Gynecol
verse relationship to body weight, being low in obese subjects and increased in anorexic subjects. SHBG may also be increased in subjects consuming a low-fat diet and in vegetarians. In the latter this may be partly from absorption of phytoestrogens in the fiber-rich diet. The level of free fatty acids in serum affects the binding of endogenous sex hormones to serum proteins and increases their biologically active unbound fractions. 29 . 3o Therefore it seems likely that contraceptive steroids, which elevate serum lipid levels, will be similarly affected. Estrogen-gestagen interactions
Interaction between the estrogen and gestagen components of combined OCs may occur both at the pharmacodynamic and pharmacokinetic levels. In respect to pharmacodynamics, the interaction may be synergistic or antagonistic, whereas in some pharacodynamic responses the two components may act independently, for example, the effect of estrogen in elevating the levels of cortisol-binding globulin or triglyceride concentrations in serum. For four monophasic combined OCs containing approximately the same dose of EE but with different gestagens, the increase in triglyceride concentrations was approximately the same. Examples of synergism between the two components would be the transformation of a proliferative into a secretory endometrium and the inhibition of ovulation. With the low doses of EE and gestagen in currently used OCs, ovulation is inhibited in almost all treatment cycles when the two components are coadministered, whereas neither component alone in the same dose would produce consistent inhibition. For most pharmacodynamic responses, the interaction is an antagonistic one, for example, the effects on high-density lipoprotein cholesterol, in which the increase produced by EE can be suppressed to a variable extent by gestagens depending on their structure and dose. The antagonistic action can clearly be seen in the effect on serum SHBG concentrations, for whereas the level of high-density lipoprotein cholesterol can be subject to many factors that may cause large variability in its measurement, serum levels of SHBG can be measured with precision and accuracy by simple methodology. As shown in Fig. 1, the SHBG concentration depends on the relative doses of estrogen (EE) and gestagen (NET) administered. Evidence is accumulating for pharmacokinetic interactions between estrogen and gestagen. One point of interaction is SHBG. As indicated above, serum SHBG level is increased by estrogens, and this may affect the pharmacokinetics of those gestagens such as LNG or gestodene (GES), which bind strongly to SHBG. 5 However, whether any clinical effects result from these changes is not clear.
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In a study in which women were sampled at intervals during 1 year of treatment with two OCS,3! serum EE concentrations were consistently higher in women receiving the OC containing GES than in those receiving desogestrel, although the dose of EE was the same in both formulations. This finding suggests that the gestagen influenced the metabolism of EE. Since EE does not bind to SHBG, changes in the serum concentration of this protein cannot account for the observed effect, and it seems likely that in women taking the GES formulation, the metabolic clearance of EE was reduced to a greater extent than in those taking EE and desogestrel. The mechanism of this effect remains to be determined but considering the effect of ethinyl steroids in decreasing the activity of cytochrome P-450 (see above), one interpretation would be that GES has more pronounced inhibitory action on cytochrome P450 than does desogestrel. In another study,32 serum EE concentrations were consistently higher as expected in women who had taken an OC for 6 months than in a control group, but the clearance rate of EE was on average 35% lower in OC users than in control subjects, suggesting a decrease in the metabolizing capacity of the OC group. In this study metabolism of concomitantly administered theophylline was also decreased, suggesting the reduction in metabolic capacity was a generalized effect; again it seems reasonable to postulate that the findings are the result of an inhibitory effect of ethinyl steroids on cytochrome P-450 activity. The increased levels of LNG in women using OCs containing EE and LNG compared with those receiving the same dose of LNG without EE has been attributed to the EE-induced increase in SHBG and the binding of LNG to SHBG, with a consequent reduction in its clearance and rate of metabolism. However, as demonstrated recently,33 this conclusion is erroneous. Thus the slower rate of metabolism of LNG on continued dosing must be the result of other factors. Another study" found that the clearance rate of LNG decreased and the half-life of elimination increased in long-term users of a OC containing LNG and EE. Therefore both of these findings suggest an increase in the resistance of LNG to metabolism on continued dosing, and again this may be the result of a decrease in the activity of the cytochrome P-450 system. In a study of the pharmacokinetics of NET and EE in a large group of women taking an OC containing these contraceptive steroids," no correlation was found between the rate of metabolism of the two steroids as measured by their half-lives of elimination. Although these two closely related steroids are metabolized by the hepatic drug-metabolizing system, this lack of correlation suggests that the metabolic reactions were catalyzed by different enzymes or different variants of cytochrome P-450.
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% Increase in Serum SHBG 200 150 100 50 Dose
100 50 50 35 35 1-19 EE 2 3 1 1 0.5 m9 NET
Fig. 1. Changes in serum SHBG concentrations in relation to dose of estrogen (EE) and gestagen (NET). (Reproduced with permission from Fotherby K. Ann NY Acad Acad Sci 1988; 538:313-20.)
Smoking
Smoking will increase the metabolism of some drugs, whereas others are unaffected. Similarly, the rate of metabolism of some endogenous steroids, such as cortisol and progesterone are reported to be increased, whereas that of others, such as estrogens and testoterone are unchanged or decreased. The cause of the variability is unclear. Smoking leads to the production of a large number of chemicals, particularly the polycyclic aromatic hydrocarbons, which are stimulators of the hepatic drug-metabolizing system. Evidence of an effect on this system is supported by the finding'6 that 2-hydroxylation of estradiol was greater in smokers (43%) than in nonsmokers (25%). In a preliminary study37 the rate of metabolism of EE and LNG was not affected by smoking, and variable results were obtained by Kanarkowski et al. '4 Clearly, definitive studies of the effect of smoking on the metabolism of contraceptive steroids are required. Conclusions
It seems clear'8. '9 that the two main areas of drug interaction that' affect the pharmacokinetics and efficacy of the OCs are first the effect of some, but not all, anticonvulsant drugs, antibiotics, and antibacterial agents on the hepatic drug-metabolizing system, which leads to an increased rate of metabolism of contraceptive steroids, and second, the effect of some, but again not all, antibiotics and antibacterial drugs on the absorption and enterohepatic circulation of contraceptive steroids; this latter effect will mainly reduce the serum concentration of EE, and the gestagen will be little affected. Effects of other therapeutic agents on contraceptive steroids are reported much more rarely, and in
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these circumstances it is difficult to know whether the reduced efficacy of the OC is caused by the concomitantly administered drug or by some other event, such as the subject forgetting to take one or more pills, particularly near the beginning or end of the treatment period, or to the infrequent but nevertheless adequately documented occurrence of ovarian activity, leading in a few instances to breakthrough ovulation and the risk of pregnancy.40,41 Even when there is the possibility of an interaction, only in a small proportion of women (probably well under 5%, although no proper epidemiologic studies have been performed to determine the incidence of drug interactions with the OCs) will the interaction occur to such an extent that there is a decrease in the efficacy of the OC, thereby leading to the risk of pregnancy. It might be expected that serious interactions would be more common now that most OCs used contain low doses of contraceptive steroids. However, there appears to be little evidence to support this contention.'9 One reason for this may be the marked interindividual variability in the pharmacokinetics of contraceptive steroids'" One might postulate that serious interactions would occur only in those women who are fast metabolizers and therefore have low serum concentrations of contraceptive steroids and in those women whose liver enzyme systems are particularly susceptible to induction. More information is required regarding the mechanisms by which contraceptive steroids produce their inhibitory effect on many coadministered drugs, and particularly since it is important with regard to longterm use of OCs, the way in which contraceptive steroids may inhibit their metabolism. REFERENCES 1. Park BK, Breckenridge AM. Clinical implications of enzyme induction. Clin Pharmacokinet 1981;6:1-24. 2. Stockley IH. Drug interactions. London: Blackwell Scientific, 1981. 3. D'Arcy PF. Drug interactions with oral contraceptives. Drug Intell Clin Pharmacol 1986;20:353-61. 4. Griffin JP, D'Arcy PF, Speirs CJ. Manual of adverse drug reactions. 4th ed. London: Wright, 1988. 5. Fotherby K. Potency and pharmacokinetics of gestagens. Contraception 1990;41 :533-50. 6. Lu AYH, West SB. Multiplicity of mammalian microsomalcytochromes P450. Pharmacol Rev 1980;31:277-92. 7. White INH. Metabolic activation of acetylenic substituents. BiochemJ 1978;174:853-61. 8. Blakey DC, White INH. Destruction of cytochrome P450 by contraceptive steroids. Biochem Pharmacol 1986;35: 1561-7. 9. Guengerich FP. Oxidation of 17a-ethynylestradiol by human liver cytochrome P450. Mol Pharmacol 1988;33: 500-8. 10. Fotherby K. Species differences in metabolism of contraceptive steroids. In: Gregoire AT, Blye RT, eds. Contraceptive steroids. New York: Plenum Press, 1986:113. II. Ortiz de Montellano PR, Correia MA. Suicidal destruction of cytochrome P450. Ann Rev Pharmacol 1983;23:481503.
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12. Koskelo P, Eisalo A, Toivonen I. Urinary excreation of porphyrin precursors in oral contraceptive users. Br Med J 1966;1:652-4. 13. White INH, Eberhard UM. Decreased liver cytochrome P450 in rates caused by norethindrone or ethynyloestradiol. BiochemJ 1977;166:57-64. 14. Peter H,Jung R, Bolt HM, Oesch F. Norethisterone and levonorgestrel oxides. J Steroid Biochem 1981; 14:83-90. 15. Schmid SE, Au WYW, Hill DE, Kadlubar FF, Shikker W. Cytochrome P450 dependent oxidation of the ethynyl group of synthetic steroids. Drug Metab Dispos 1983;11: 531-6. 16. Field B, Lu C, Hepner GW. Inhibition of hepatic drug metabolism by norethindrone. Clin Pharmacol Ther 1979;25:196-8. 17. Mills TM, Lin TJ, Hemandy S, Greenblatt RB, Ellegood JO, Mahesh VB. MCR and urinary excretion of norethindrone. AMJ OBSTET GYNECOL 1974;120:764-72. 18. Anderson KE. Influences of diet and nutrition on clinical pharmacokinetics. Clin Pharmacokinet 1988; 14:325-46. 19. Welling PG. Influence of food and diet on drug absorption.J Pharmacokinet Biochem 1977;5:291-334. 20. Melander A, McLean A. Influence of food intake on presystemic clearance of drugs. Clin Pharamcokinet 1983;8: 286-96. 21. Fotherby K, Koetsawang S. Metabolism of injectable contraceptive steroids in obese and thin women. Contraception 1982;26:51-8. 22. Prasad KVS, Rao BSN, Sivakumar B, Prema K. Pharmacokinetics of norethindrone in Indian women. Contraception 1979;20:77-90. 23. Madharan NK, Sirakumar B, Prema K, Rao BSN. Pharmacokinetics of levonorgestrel in Indian women. Contraception 1979;20:303-12. 24. Fishman J, Bradlow HL. Effect of malnutrition of the metabolism of sex hormones. Clin Pharmacol Ther 1977;22:721-8. 25. Longcope C, Gorbach S, Goldin S, et al. Effect of a low fat diet on oestrogen metabolism. J Clin Endocrinol Metab 1987;64: 1246-9. 26. Belanger A, Locung A, Noel C, et al. Influence of diet on plasma steroid and SHBG levels. J Steroid Biochem 1989;32:829-33. 27. Aldercruetz H, Hockerstedt K, Bannwart C, et al. Effect of dietary components on liver metabolism of estrogens. J Steroid Biochem 1987;27:1135-44. 28. Prasad RNV, Fotherby K, Jenkins N, Ratnam SS. Single dose kinetics of norethisterone in lactovegetarians. Singapore J Obstet Gynaecol 1981; 12:59-67. 29. Reed MJ, Beranek PA, Cheng RW,James VHT. Free fatty acids, a possible regular of available oestradiol fractions. J Steroid Biochem 1986;24:657-9. 30. Mooradian AD, Pamplona DM, Viosea SP, Korenman SC. Effect of free fatty acids on bioavailability of plasma testroterone. J Steroid Biochem 1988;29:369-70. 31. Jung-Hoffman C, Kuhl H. Interaction with the pharmacokinetics of ethynyloestradiol of progestogens in oral contraceptives. Contraception 1989;40:299-312. 32. Tornatore KM, Kanarkowski R, McCarthy TL, Gardner MJ, Yarchak AM, J usko WJ. Effect of chronic OC steroids on theophylline disposition. Eur J Clin Pharmacol 1982; 23: 129-34. 33. Fotherby K. Pharmacokinetics of gestagens-some problems. AM J OBSTET GYNECOL 1990;163:323-8. 34. Kanarkowski R, Tornatore KM, Ambrosio R, Gardner MJ, Jusko WJ. Pharmacokinetics of single and multiple doses ofEE and LNG. Clin Pharmacol Ther 1988;43:2331. 35. Shi YE, He CH, Gu J, Fotherby K. Pharmacokinetics of norethisterone in humans. Contraception 1987;35:46575. 36. Michnovicz JJ, Herschcopf RJ, Haley NJ, Bradlow HL,
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Fishman J. Cigarette smoking alters hepatic estrogen metabolism. Metabolism 1989;38:537-41. 37. Crawford P, Back DJ, Orme ML, Breckenridge AM. Oral contraceptive steroid plasma concentrations in smokers and non-smokers. Br Med J 1981 ;282: 1829-30. 38. Back DJ, Grimmer SF, Otma ML, Proudlove C, Mann RD, Breckenridge AM. Evaluation of reports on oral contraceptive-drug interactions. Br J Clin Pharmacol 1988;25:527 -32. 39. Szoka PR, Edgren RA. Drug interactions with oral contraceptives. Fertil Steril 1988;49:315-85.
40. Westcombe R, Ellis R, Fotherby K. Suppression of ovulation in women using a triphasic oral contraceptive. Br J Fam Plann 1987;13:127-32. 41. Sparrow MJ. Pill method failures. NZ Med J 1987;100: 102-5. 42. Fotherby K. Variability of pharmacokinetic parameters for contraceptive steroids. J Steroid Biochem 1983; 19: 817-20. 43. Fotherby K. Interactions of contraceptive steroids with steroid binding proteins and the clinical implications. Ann NY Acad Sci 1988;538:313-20.
Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs F. Peter Guengerich, PhD Nashville, Tennessee The major 17a-ethinyl estradiol 2-hydroxylase is humans is the hepatic enzyme cytochrome P-450 II1A4 (P-450NF), which is known to be inducible by rifampicin or barbiturates. The literature indicates that 17j3-estradiol, progesterone, and norgestrel are competitive inhibitors and that primaquine and tolbutamide are rather weak noncompetitive inhibitors. Recent experiments in this laboratory indicate that gestodene is a relatively potent mechanism-based inactivator of cytochrome P-450 IIIA4 in vitro. Inhibition requires incubation with the reduced form of nicotinamide adenine dinucleotide phosphate, is time and concentration dependent, and can be partially blocked by the presence of non inhibitory cytochrome P-450 II1A4 substrates. The in vitro activation by gestodene provides a possible explanation for the increase in plasma estrogen levels reported in women administered gestodene along with 17a-ethinyl estradiol. (AM J OSSTET GYNECOL 1990;163:2159-63.)
Key words: 17a-Ethinyl estradiol, 2-hydroxylation, gestodene, inhibition, of enzymes, cytochrome P-4S0 IIIA4 The main estrogenic component of oral contraceptives is 17a-ethinyl estradiol, which was introduced by Innhoffen and Hohlweg.' Its usefulness appears to result from its slow elimination relative to 1713-estradiol. Considerable variation is seen in the rates of clearance of ethinyl estradiol among women," 1 and such differences cause difficulty in adjusting the drug level. In addition to the normal variation seen among persons, another problem is introduced by the induction and inhibition of enzymes involved in the metabolism of ethinyl estradiol. 2-Hydroxy ethinyl estradiol, the ma-
jor product, is also estrogenic but is not retained in the body as long as the parent compound. Menstrual problems and unexpected pregnancies have been experienced in some women using rifampicin or barbituates, and the effects can be rationalized in the decreased levels of ethinyl estradiol measured both in vivo and in vitro,"" Bolt et al." also demonstrated that rates of hydroxylation of estradiol were increased in women after treatment with rifampicin, with the effect presumably caused by enzyme induction.
Identification of cytochrome P-450NF as ethinyl estradiol 2-hydroxylase From the Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine. Supported in part by U.S. Public Health Service grants CA44353 and £S00267. Reprint requests: F. Peter Guengerich, PhD, Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University Selwol of Medicine, Nashville, TN 37232.
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Human liver P-4S0NF was first isolated as the enzyme catalyzing the oxidation of the calcium channel blocker nifedipine. lU In that study the enzyme was also the principal catalyst in the main pathways of testosterone and estradiol metabolism in human liver, namely, 613- and 2-hydroxylation, respectively. Further studies in this
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Interactions with oral contraceptives Kenneth Fotherby, PhD London, England The interaction of a range of different factors with the pharmacologic activity of oral contraceptives is reviewed. Pharmacokinetic interactions with oral contraceptives may occur (1) during absorption and extrahepatic circulation, (2) by interfering with protein binding, and (3) during hepatic metabolism. The hepatic mixed function oxidase system, which is mainly responsible for the metabolism of oral contraceptives, is affected by several different factors and is easily induced. Nutrition affects the activity of many drugs, but information regarding oral contraceptives is meager. Both pharmacokinetic and pharmacodynamic interactions, which may be synergistic or antagonistic, between the estrogen and gestagen components of oral contraceptives, are important, but there is no correlation between the rate of metabolism of the two components. Evidence suggests that some anticonvulsant, antibiotic, and antibacterial drugs may reduce the efficacy of oral contraceptives. Instances of interactions of other therapeutic agents are reported infrequently. The incidence of serious interactions is low and does not appear to have been reduced with low-dose oral contraceptives, probably because of large intersubject variability in the pharmacokinetics of oral contraceptives. (AM J OBSTET GVNECOL 1990;163:2153-9.)
Key words: Drug interactions, oral contraceptives, pharmacokinetics, absorption, protein binding, metabolism Considering (1) the wide variety of drugs available, (2) the large proportion of the population consuming both prescribed and over-the-counter drugs, (3) that nutritional factors may affect drug action, and (4) that many drugs have similar metabolic pathways, it is perhaps surprising that drug interactions are not more common than they appear to be. This article is concerned only with the effects of other agents on the biologic activity of contraceptive steroids, and will not examine the changes in drug activity that may be encountered in women using oral contraceptives (OCs). As far as contraceptive steroids are concerned, a clinically important decrease in their efficacy because of interaction with other drugs appears to occur in a very small minority of women «5%), and the possible reasons why the incidence is so low are considered later. This article examines only the possible loci in the metabolism of contraceptive steroids in which other drugs and nutrients might interact. A detailed listing of all the drugs likely to interact with the contraceptive steroids will not be provided, since many excellent accounts of this area are available. 1-4 The interaction of drugs and nutrients with OCs may interfere with their pharmacokinetic behavior, phar-
From the Department of Steroid Biochemistry, Royal Postgraduate Medical School, Hammersmith Hospital. Reprints are not available.
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macodynamic actions, or both. In addition, with combined OCs the interaction of the estrogen and gestagen components is of great importance. Pharmacokinetic interactions
The three main areas in which pharmacokinetic interactions may occur between contraceptive steroids and other drugs are (1) absorption, (2) serum protein binding, and (3) hepatic metabolism. Absorption. There are two mechanisms by which drugs may interact with the absorption of contraceptive steroids: by affecting the absorptive process itself or by affecting the intestinal flora. Absorption of steroids may be impaired when the rate of which they pass through the gastrointestinal tract is markedly increased because of increased intestinal motility; for example, in subjects either using laxatives or with severe or prolonged diarrhea. Ethinyl estradiol (EE) and some gestagens, such as norethisterone (NET), undergo extensive (40% to 60%) firstpass metabolism, much of which occurs in the intestinal wall. Absorption appears to occur mainly in the upper part of the intestine, since the bioavailability of EE and levonorgestrel (LNG) is not decreased by ileostomy or after jejunoileal bypass. Phase 1 metabolism of steroids can be demonstrated with intestinal tissue in vitro, and intestinal tissue contains cytochrome P-450, but under normal in vitro conditions, phase 1 metabolism by the intestine appears to be unimportant. However, the ex-
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tent to which such metabolism is increased after the administration of enzyme-inducing drugs has not been investigated. Specific effects on EE, which undergoes sulfation in the intestinal mucosa, may occur with certain drugs. Since the amount of available sulfate appears to be limited, administration in high doses of other drugs that are sulfated during absorption, such as vitamin C and paracetamol, leads to competition, less EE is sulfated, and its bioavailability is improved. Conversely, when the competing drug is stopped, more sulfation of EE occurs and its bioavailability is reduced. Contraceptive steroids also undergo an enterohepatic circulation, and this is particularly important for EE. The steroids conjugated in the liver are secreted into the intestine by way of bile and are hydrolyzed by the gut flora. If these are inhibited by the administration of antibiotics, hydrolysis of the cOrUugates is markedly reduced, which leads to reduced reabsorption of the steroids and an increase in the fecal excretion. The effects on the gestagens are clinically less important, since they are rapidly metabolized to biologically inactive products by the liver, mainly by reduction, and to a lesser extent by hydroxylation before conjugation and secretion in the bile. Metabolism of EE in the liver involves hydroxylation at various positions, and in subjects who are poor hydroxylators, more EE is available for conjugation and the extrahepatic circulation. In these subjects interference with the extrahepatic circulation produced by the administration of antibiotics may lead to markedly lower serum EE concentrations. Although the effect of some antibiotics on the gut flora provides one mechanism by which the bioavailability of contraceptive steroids, particularly EE, may be decreased, whether this is the major factor involved in the few clinically important interactions that occur remains to be conclusively demonstrated. Binding to serum proteins. The contraceptive steroids are highly bound (>95%) in blood and thus are susceptible to factors that may produce only slight modifications of the binding. Thus an insignificant 2% decrease in the amount bound could lead to a significant 50% increase in the unbound fraction on which the biologic activity of the steroids depends. EE binds only to albumin, and although interaction between drugs in respect to albumin has been demonstrated, no interaction between contraceptive steroids and this protein appears to have been reported. However, the gestagens bind both to albumin and sex hormone-binding globulin (SHBG), the extent and tightness of the binding to SHBG depending on their structure, and there is a complex equilibrium between the different fractions. Serum SHBG levels can be increased by the administration of estrogens and several other drugs. The in-
December 1990 Am J Obstet Gynecol
crease in SHBG may lead to an increase in the SHBG bound fraction, mainly at the expense of the albumin bound, from which dissociation occurs readily. Because contraceptive steroids are administered on a continuing basis, their serum concentrations will increase until a steady state is reached and a fresh equilibrium is formed among the different fractions; at this point the proportion unbound may be decreased, but the concentration of unbound may be unchanged. Therefore although there may be marked changes in the relative binding, these changes are unlikely to influence the efficacy of contraceptive steroids. These interactions between estrogen, gestagens, and SHBG are considered in more detail in a recent article.' Hepatic metabolism. The most important locus of drug interaction appears to be the mixed function oxidase system of the liver endoplasmic reticulum. This system occurs in several other tissues, but for most drugs the liver is the major site. The enzyme system has a low specificity, performing a number of different metabolic transformations, all of which involve cytochrome P-450, cytochrome C reductase, a flavoprotein, and reduced nicotinamide adenine dinucleotide phosphate, and its activity is stimulated by many drugs. As a result, not only is the administered drug metabolized more quickly, with a decrease in its blood concentration and biologic activity, but so are several other drugs that may be administered concurrently. There are a number of distinct P-450s," each of which may be under separate genetic control, and this may account for some of the interindividual variability in the rate of drug metabolism. The low specificity of the enzyme system as a whole enables it to metabolize a large number of different drugs and endogenous compounds, including the gonadal and adrenocortical steroids. Each of the distinct cytochrome P-450s may exert its main activity toward groups of substrates, with a variable amount of overlap between groups, and this accounts for the competitive inhibition that can occur among different substrates. In addition to genetic factors, the rate of drug metabolism is influenced by a large number of environmental factors, diet, alcohol use, smoking, medication, and pathologic conditions, and all these various factors may affect the mixed function oxidase activity of the liver. Despite the low or overlapping specificity of the mixed function oxidase system, there is often marked selectively, both positional and stereochemically, in the metabolism of the substrate. With the steroids, which can be oxidized at several different sites in the molecule, the resulting hydroxylations occur to a variable extent and they can be inhibited differently by various factors. Again this suggests that multiple forms of cytochrome P-450 are present with different specifications. The relative activities of the different cytochrome P-450s ap-
Volume 163 Number 6, Part 2
pear to vary among subjects, and if so, it is important in accounting for much of the interindividual variation in drug metabolism. The increase in the activity of the mixed function oxidase system produced by the administration of an inducing drug leads to an increase in the rate of metabolism of any contraceptive steroid the subject may use, so that the half-life of elimination of the steroid, and consequently its serum concentration and biologic effect, are decreased. Conversely, the administration of contraceptive steroids usually has an inhibitory effect on the metabolism of other drugs, which leads to an increase in their pharmacologic activity.3 The mechanism of this inhibitory effect in humans is not entirely clear. In animals, mainly the rat, the administration of steroids containing the ethinyl group, which encompasses most of the contraceptive steroids currently used, appears to inactivate cytochrome P-450, with a consequent decrease in the drug-metabolizing capacity of the liver. It was first demonstrated in humans in 1969 that EE may be metabolized by way of oxidation of the ethinyl group, which results in the formation of o-homosteroids and small amounts of estrone and estradiol. The oxidation of the ethinyl group is a complex reaction involving the production of numerous reactive intermediates. It appears that one or more of these metabolites interacts with, and leads to the destruction of, the heme group of cytochrome P450, with a consequent loss of its drug-metabolizing activity both toward the steroid and other administered drugs metabolized by the mixed function oxidase system. 7.9 As a result, the pharmacologic effect of such drugs is increased. There is evidence of the in vitro formation of o-homosteroids from ethinyl steroids in the rabbit and monkey, in addition to humans. 1O Several other chemical structures, in addition to the ethinyl group, may have a similar destructive effect on cytochrome P-450. II An increased excretion of porphyrin precursors and coproporphyrin was reported to occur in women taking OCS,I2 which could indicate an increased turnover of cytochrome P-450 heme. One reactive intermediate in the oxidation of the ethinyl group is an epoxide, and these compounds may also be formed by oxidation at the carbon 4-5 double bond of the steroids." Interestingly, the epoxides of norethisterone (NET) and levonorgestrel (LNG) may show differences in their biologic activities. I4 However, these epoxides do not appear to be implicated in heme destruction, so that the effect produced by oxidation of the ethinyl group must be from some other reactive intermediate. Many questions still remain to be answered in respect to the inhibition of cytochrome P450. Destruction appears to apply only to the heme part, which could readily be resynthesized; the apoprotein appears to be unaffected. So far heme de-
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struction has been demonstrated only in the rat and in in vitro studies; whether it occurs and to what extent in humans remains to be determined. In women metabolism of the ethinyl group is only a minor pathway for EE and probably even less so for NET and LNG. Destruction of cytochrome P-450 by metabolites of the ethinyl steroids provides one mechanism by which contraceptive steroids may impair the metabolism of coadministered drugs. Whether the concentration of the reactive intermediates attains a level sufficient to impair the cytochrome P-450 system with short-term administration of contraceptive steroids seems unlikely, although drug interactions may occur under these conditions. However, with long-term use of steroidal contraception, the situation may be different. A decreased concentration of cytochrome P-450 was found in liver microsomes from monkeys that had received contraception steroids for at least 10 years,I5 although the factors responsible need to be identified. Even if heme destruction by contraceptive steroids with a consequent reduction in the drug-metabolizing capacity of the liver occurs in humans, it does not rule out the possibility that other mechanisms may exist and may be more important for the steroidal inhibition of drug metabolism. Even small doses of gestagens administered without estrogen may inhibit drug metabolism. I6 Conversely, Mills et al. I7 reported that the clearance of NET increased in women treated with 2.5 mg of NET daily. Any of these mechanisms provides a means by which contraceptive steroids are able to inhibit their metabolism, with a consequent increase over time in the pharmacologic effects. Nutritional effects
In considering nutritional effects, it is necessary to distinguish between effects related to the quantity of the diet and those related to its quality. The former will depend on whether caloric intake in relation to energy expenditure is very low, leading to a low body mass index (BMI) and in extreme cases to anorexia nervosa, or very high, leading a high BMI and obesity. The quality will depend on the composition of a diet that is satisfactory in relation to caloric requirements. The influence of diet and nutrition on the clinical pharmacokinetics of drugs in general has been reviewed. IS Food intake affects absorption and bioavailability of several drugs I9. 2o but little information is available regarding contraceptive steroids. Absorption of some lipid-soluble drugs is increased by a high-fat diet, but no investigations have been performed to determine whether this also applies to lipidsoluble contraceptive steroids. The pharmacokinetics of many drugs may be altered in obese subjects, particularly lipid-soluble drugs such as steroids, for which the apparent volume of distribution may be greatly
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increased. However, in a preliminary comparison of two gestagens in healthy subjects, medroxyprogesterone acetate and NET enanthate given by intramuscular injection so that the effects of intestinal absorption were eliminated, differences in the pharmacokinetics between obese (BMI > 28) and thin (BMI < 20) subjects were minimal. 21 The elimination half-life of NET was significantly lower (mean, 5.9 hours) in a group of Indian women in a low socioeconomic group with poor nutritional status compared with that (13.4 hours) of well-nourished women in a high socioeconomic group.22 Similar findings have also been reported for LNG. 23 The extent to which these findings can be ascribed to low serum protein levels in the former group remains to be determined. In a preliminary study of estradiol, and presumably the same situation holds for EE, 2-hydroxylation was increased and 16cx-hydroxylation was decreased in anorexic subjects, whereas the reverse was observed in obese subjects. 24 High-protein diets appear to stimulate the activity of the hepatic drug-oxidizing system, with a consequent increased rate of metabolism of many drugs. The 2-hydrozylation of estradiol is enhanced but apparently without any concomitant change in 16cxhydrozylation,18 and the activity of the hepatic 5cxreductase is decreased. High-carbohydrate diets decrease 2-hydrozylation. A low-fat diet was also reported to increase 2-hydroxylation of estradiol and to decrease 16cx-hydroxylation!5 although this diet was also probably a high-protein one. Diet also has a marked influence on endogenously secreted androgens in humans,26 and by analogy might be expected to affect the metabolism of gestagens. Certain specific nutrients, such as charcoal-broiled beef and cruciferous vegetables, stimulate the hepatic mixed function oxidase system. Whether metabolism of contraceptive steroids differs between vegetarians and nonvegetarians is still controversial. Vegetarian diets tend to contain less fat and more fiber than nonvegetarian diets, and these differences appear to influence the metabolism of endogenous estrogens, which leads to a decrease in plasma estradiol concentrations. 27 This decrease might be partly caused by a decrease in the enterohepatic circulation. However, there were no significant differences in the pharmacokinetics of NET between lactovegetarian and nonvegetarian women. 28 One determinant of whether there are differences in drug metabolism between vegetarians and non vegetarians appears to be the amount of protein in the diet. In many of the situations discussed above, changes occur in serum SHBG concentrations, and while these changes will not affect EE, which does not bind to SHBG, they will affect the unbound biologically active fraction of the gestagens. Serum SHBG shows an in-
December 1990 Am J Obstet Gynecol
verse relationship to body weight, being low in obese subjects and increased in anorexic subjects. SHBG may also be increased in subjects consuming a low-fat diet and in vegetarians. In the latter this may be partly from absorption of phytoestrogens in the fiber-rich diet. The level of free fatty acids in serum affects the binding of endogenous sex hormones to serum proteins and increases their biologically active unbound fractions. 29 . 3o Therefore it seems likely that contraceptive steroids, which elevate serum lipid levels, will be similarly affected. Estrogen-gestagen interactions
Interaction between the estrogen and gestagen components of combined OCs may occur both at the pharmacodynamic and pharmacokinetic levels. In respect to pharmacodynamics, the interaction may be synergistic or antagonistic, whereas in some pharacodynamic responses the two components may act independently, for example, the effect of estrogen in elevating the levels of cortisol-binding globulin or triglyceride concentrations in serum. For four monophasic combined OCs containing approximately the same dose of EE but with different gestagens, the increase in triglyceride concentrations was approximately the same. Examples of synergism between the two components would be the transformation of a proliferative into a secretory endometrium and the inhibition of ovulation. With the low doses of EE and gestagen in currently used OCs, ovulation is inhibited in almost all treatment cycles when the two components are coadministered, whereas neither component alone in the same dose would produce consistent inhibition. For most pharmacodynamic responses, the interaction is an antagonistic one, for example, the effects on high-density lipoprotein cholesterol, in which the increase produced by EE can be suppressed to a variable extent by gestagens depending on their structure and dose. The antagonistic action can clearly be seen in the effect on serum SHBG concentrations, for whereas the level of high-density lipoprotein cholesterol can be subject to many factors that may cause large variability in its measurement, serum levels of SHBG can be measured with precision and accuracy by simple methodology. As shown in Fig. 1, the SHBG concentration depends on the relative doses of estrogen (EE) and gestagen (NET) administered. Evidence is accumulating for pharmacokinetic interactions between estrogen and gestagen. One point of interaction is SHBG. As indicated above, serum SHBG level is increased by estrogens, and this may affect the pharmacokinetics of those gestagens such as LNG or gestodene (GES), which bind strongly to SHBG. 5 However, whether any clinical effects result from these changes is not clear.
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Volume 163 Number 6, Part 2
In a study in which women were sampled at intervals during 1 year of treatment with two OCS,3! serum EE concentrations were consistently higher in women receiving the OC containing GES than in those receiving desogestrel, although the dose of EE was the same in both formulations. This finding suggests that the gestagen influenced the metabolism of EE. Since EE does not bind to SHBG, changes in the serum concentration of this protein cannot account for the observed effect, and it seems likely that in women taking the GES formulation, the metabolic clearance of EE was reduced to a greater extent than in those taking EE and desogestrel. The mechanism of this effect remains to be determined but considering the effect of ethinyl steroids in decreasing the activity of cytochrome P-450 (see above), one interpretation would be that GES has more pronounced inhibitory action on cytochrome P450 than does desogestrel. In another study,32 serum EE concentrations were consistently higher as expected in women who had taken an OC for 6 months than in a control group, but the clearance rate of EE was on average 35% lower in OC users than in control subjects, suggesting a decrease in the metabolizing capacity of the OC group. In this study metabolism of concomitantly administered theophylline was also decreased, suggesting the reduction in metabolic capacity was a generalized effect; again it seems reasonable to postulate that the findings are the result of an inhibitory effect of ethinyl steroids on cytochrome P-450 activity. The increased levels of LNG in women using OCs containing EE and LNG compared with those receiving the same dose of LNG without EE has been attributed to the EE-induced increase in SHBG and the binding of LNG to SHBG, with a consequent reduction in its clearance and rate of metabolism. However, as demonstrated recently,33 this conclusion is erroneous. Thus the slower rate of metabolism of LNG on continued dosing must be the result of other factors. Another study" found that the clearance rate of LNG decreased and the half-life of elimination increased in long-term users of a OC containing LNG and EE. Therefore both of these findings suggest an increase in the resistance of LNG to metabolism on continued dosing, and again this may be the result of a decrease in the activity of the cytochrome P-450 system. In a study of the pharmacokinetics of NET and EE in a large group of women taking an OC containing these contraceptive steroids," no correlation was found between the rate of metabolism of the two steroids as measured by their half-lives of elimination. Although these two closely related steroids are metabolized by the hepatic drug-metabolizing system, this lack of correlation suggests that the metabolic reactions were catalyzed by different enzymes or different variants of cytochrome P-450.
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% Increase in Serum SHBG 200 150 100 50 Dose
100 50 50 35 35 1-19 EE 2 3 1 1 0.5 m9 NET
Fig. 1. Changes in serum SHBG concentrations in relation to dose of estrogen (EE) and gestagen (NET). (Reproduced with permission from Fotherby K. Ann NY Acad Acad Sci 1988; 538:313-20.)
Smoking
Smoking will increase the metabolism of some drugs, whereas others are unaffected. Similarly, the rate of metabolism of some endogenous steroids, such as cortisol and progesterone are reported to be increased, whereas that of others, such as estrogens and testoterone are unchanged or decreased. The cause of the variability is unclear. Smoking leads to the production of a large number of chemicals, particularly the polycyclic aromatic hydrocarbons, which are stimulators of the hepatic drug-metabolizing system. Evidence of an effect on this system is supported by the finding'6 that 2-hydroxylation of estradiol was greater in smokers (43%) than in nonsmokers (25%). In a preliminary study37 the rate of metabolism of EE and LNG was not affected by smoking, and variable results were obtained by Kanarkowski et al. '4 Clearly, definitive studies of the effect of smoking on the metabolism of contraceptive steroids are required. Conclusions
It seems clear'8. '9 that the two main areas of drug interaction that' affect the pharmacokinetics and efficacy of the OCs are first the effect of some, but not all, anticonvulsant drugs, antibiotics, and antibacterial agents on the hepatic drug-metabolizing system, which leads to an increased rate of metabolism of contraceptive steroids, and second, the effect of some, but again not all, antibiotics and antibacterial drugs on the absorption and enterohepatic circulation of contraceptive steroids; this latter effect will mainly reduce the serum concentration of EE, and the gestagen will be little affected. Effects of other therapeutic agents on contraceptive steroids are reported much more rarely, and in
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these circumstances it is difficult to know whether the reduced efficacy of the OC is caused by the concomitantly administered drug or by some other event, such as the subject forgetting to take one or more pills, particularly near the beginning or end of the treatment period, or to the infrequent but nevertheless adequately documented occurrence of ovarian activity, leading in a few instances to breakthrough ovulation and the risk of pregnancy.40,41 Even when there is the possibility of an interaction, only in a small proportion of women (probably well under 5%, although no proper epidemiologic studies have been performed to determine the incidence of drug interactions with the OCs) will the interaction occur to such an extent that there is a decrease in the efficacy of the OC, thereby leading to the risk of pregnancy. It might be expected that serious interactions would be more common now that most OCs used contain low doses of contraceptive steroids. However, there appears to be little evidence to support this contention.'9 One reason for this may be the marked interindividual variability in the pharmacokinetics of contraceptive steroids'" One might postulate that serious interactions would occur only in those women who are fast metabolizers and therefore have low serum concentrations of contraceptive steroids and in those women whose liver enzyme systems are particularly susceptible to induction. More information is required regarding the mechanisms by which contraceptive steroids produce their inhibitory effect on many coadministered drugs, and particularly since it is important with regard to longterm use of OCs, the way in which contraceptive steroids may inhibit their metabolism. REFERENCES 1. Park BK, Breckenridge AM. Clinical implications of enzyme induction. Clin Pharmacokinet 1981;6:1-24. 2. Stockley IH. Drug interactions. London: Blackwell Scientific, 1981. 3. D'Arcy PF. Drug interactions with oral contraceptives. Drug Intell Clin Pharmacol 1986;20:353-61. 4. Griffin JP, D'Arcy PF, Speirs CJ. Manual of adverse drug reactions. 4th ed. London: Wright, 1988. 5. Fotherby K. Potency and pharmacokinetics of gestagens. Contraception 1990;41 :533-50. 6. Lu AYH, West SB. Multiplicity of mammalian microsomalcytochromes P450. Pharmacol Rev 1980;31:277-92. 7. White INH. Metabolic activation of acetylenic substituents. BiochemJ 1978;174:853-61. 8. Blakey DC, White INH. Destruction of cytochrome P450 by contraceptive steroids. Biochem Pharmacol 1986;35: 1561-7. 9. Guengerich FP. Oxidation of 17a-ethynylestradiol by human liver cytochrome P450. Mol Pharmacol 1988;33: 500-8. 10. Fotherby K. Species differences in metabolism of contraceptive steroids. In: Gregoire AT, Blye RT, eds. Contraceptive steroids. New York: Plenum Press, 1986:113. II. Ortiz de Montellano PR, Correia MA. Suicidal destruction of cytochrome P450. Ann Rev Pharmacol 1983;23:481503.
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12. Koskelo P, Eisalo A, Toivonen I. Urinary excreation of porphyrin precursors in oral contraceptive users. Br Med J 1966;1:652-4. 13. White INH, Eberhard UM. Decreased liver cytochrome P450 in rates caused by norethindrone or ethynyloestradiol. BiochemJ 1977;166:57-64. 14. Peter H,Jung R, Bolt HM, Oesch F. Norethisterone and levonorgestrel oxides. J Steroid Biochem 1981; 14:83-90. 15. Schmid SE, Au WYW, Hill DE, Kadlubar FF, Shikker W. Cytochrome P450 dependent oxidation of the ethynyl group of synthetic steroids. Drug Metab Dispos 1983;11: 531-6. 16. Field B, Lu C, Hepner GW. Inhibition of hepatic drug metabolism by norethindrone. Clin Pharmacol Ther 1979;25:196-8. 17. Mills TM, Lin TJ, Hemandy S, Greenblatt RB, Ellegood JO, Mahesh VB. MCR and urinary excretion of norethindrone. AMJ OBSTET GYNECOL 1974;120:764-72. 18. Anderson KE. Influences of diet and nutrition on clinical pharmacokinetics. Clin Pharmacokinet 1988; 14:325-46. 19. Welling PG. Influence of food and diet on drug absorption.J Pharmacokinet Biochem 1977;5:291-334. 20. Melander A, McLean A. Influence of food intake on presystemic clearance of drugs. Clin Pharamcokinet 1983;8: 286-96. 21. Fotherby K, Koetsawang S. Metabolism of injectable contraceptive steroids in obese and thin women. Contraception 1982;26:51-8. 22. Prasad KVS, Rao BSN, Sivakumar B, Prema K. Pharmacokinetics of norethindrone in Indian women. Contraception 1979;20:77-90. 23. Madharan NK, Sirakumar B, Prema K, Rao BSN. Pharmacokinetics of levonorgestrel in Indian women. Contraception 1979;20:303-12. 24. Fishman J, Bradlow HL. Effect of malnutrition of the metabolism of sex hormones. Clin Pharmacol Ther 1977;22:721-8. 25. Longcope C, Gorbach S, Goldin S, et al. Effect of a low fat diet on oestrogen metabolism. J Clin Endocrinol Metab 1987;64: 1246-9. 26. Belanger A, Locung A, Noel C, et al. Influence of diet on plasma steroid and SHBG levels. J Steroid Biochem 1989;32:829-33. 27. Aldercruetz H, Hockerstedt K, Bannwart C, et al. Effect of dietary components on liver metabolism of estrogens. J Steroid Biochem 1987;27:1135-44. 28. Prasad RNV, Fotherby K, Jenkins N, Ratnam SS. Single dose kinetics of norethisterone in lactovegetarians. Singapore J Obstet Gynaecol 1981; 12:59-67. 29. Reed MJ, Beranek PA, Cheng RW,James VHT. Free fatty acids, a possible regular of available oestradiol fractions. J Steroid Biochem 1986;24:657-9. 30. Mooradian AD, Pamplona DM, Viosea SP, Korenman SC. Effect of free fatty acids on bioavailability of plasma testroterone. J Steroid Biochem 1988;29:369-70. 31. Jung-Hoffman C, Kuhl H. Interaction with the pharmacokinetics of ethynyloestradiol of progestogens in oral contraceptives. Contraception 1989;40:299-312. 32. Tornatore KM, Kanarkowski R, McCarthy TL, Gardner MJ, Yarchak AM, J usko WJ. Effect of chronic OC steroids on theophylline disposition. Eur J Clin Pharmacol 1982; 23: 129-34. 33. Fotherby K. Pharmacokinetics of gestagens-some problems. AM J OBSTET GYNECOL 1990;163:323-8. 34. Kanarkowski R, Tornatore KM, Ambrosio R, Gardner MJ, Jusko WJ. Pharmacokinetics of single and multiple doses ofEE and LNG. Clin Pharmacol Ther 1988;43:2331. 35. Shi YE, He CH, Gu J, Fotherby K. Pharmacokinetics of norethisterone in humans. Contraception 1987;35:46575. 36. Michnovicz JJ, Herschcopf RJ, Haley NJ, Bradlow HL,
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Fishman J. Cigarette smoking alters hepatic estrogen metabolism. Metabolism 1989;38:537-41. 37. Crawford P, Back DJ, Orme ML, Breckenridge AM. Oral contraceptive steroid plasma concentrations in smokers and non-smokers. Br Med J 1981 ;282: 1829-30. 38. Back DJ, Grimmer SF, Otma ML, Proudlove C, Mann RD, Breckenridge AM. Evaluation of reports on oral contraceptive-drug interactions. Br J Clin Pharmacol 1988;25:527 -32. 39. Szoka PR, Edgren RA. Drug interactions with oral contraceptives. Fertil Steril 1988;49:315-85.
40. Westcombe R, Ellis R, Fotherby K. Suppression of ovulation in women using a triphasic oral contraceptive. Br J Fam Plann 1987;13:127-32. 41. Sparrow MJ. Pill method failures. NZ Med J 1987;100: 102-5. 42. Fotherby K. Variability of pharmacokinetic parameters for contraceptive steroids. J Steroid Biochem 1983; 19: 817-20. 43. Fotherby K. Interactions of contraceptive steroids with steroid binding proteins and the clinical implications. Ann NY Acad Sci 1988;538:313-20.
Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs F. Peter Guengerich, PhD Nashville, Tennessee The major 17a-ethinyl estradiol 2-hydroxylase is humans is the hepatic enzyme cytochrome P-450 II1A4 (P-450NF), which is known to be inducible by rifampicin or barbiturates. The literature indicates that 17j3-estradiol, progesterone, and norgestrel are competitive inhibitors and that primaquine and tolbutamide are rather weak noncompetitive inhibitors. Recent experiments in this laboratory indicate that gestodene is a relatively potent mechanism-based inactivator of cytochrome P-450 IIIA4 in vitro. Inhibition requires incubation with the reduced form of nicotinamide adenine dinucleotide phosphate, is time and concentration dependent, and can be partially blocked by the presence of non inhibitory cytochrome P-450 II1A4 substrates. The in vitro activation by gestodene provides a possible explanation for the increase in plasma estrogen levels reported in women administered gestodene along with 17a-ethinyl estradiol. (AM J OSSTET GYNECOL 1990;163:2159-63.)
Key words: 17a-Ethinyl estradiol, 2-hydroxylation, gestodene, inhibition, of enzymes, cytochrome P-4S0 IIIA4 The main estrogenic component of oral contraceptives is 17a-ethinyl estradiol, which was introduced by Innhoffen and Hohlweg.' Its usefulness appears to result from its slow elimination relative to 1713-estradiol. Considerable variation is seen in the rates of clearance of ethinyl estradiol among women," 1 and such differences cause difficulty in adjusting the drug level. In addition to the normal variation seen among persons, another problem is introduced by the induction and inhibition of enzymes involved in the metabolism of ethinyl estradiol. 2-Hydroxy ethinyl estradiol, the ma-
jor product, is also estrogenic but is not retained in the body as long as the parent compound. Menstrual problems and unexpected pregnancies have been experienced in some women using rifampicin or barbituates, and the effects can be rationalized in the decreased levels of ethinyl estradiol measured both in vivo and in vitro,"" Bolt et al." also demonstrated that rates of hydroxylation of estradiol were increased in women after treatment with rifampicin, with the effect presumably caused by enzyme induction.
Identification of cytochrome P-450NF as ethinyl estradiol 2-hydroxylase From the Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine. Supported in part by U.S. Public Health Service grants CA44353 and £S00267. Reprint requests: F. Peter Guengerich, PhD, Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University Selwol of Medicine, Nashville, TN 37232.
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Human liver P-4S0NF was first isolated as the enzyme catalyzing the oxidation of the calcium channel blocker nifedipine. lU In that study the enzyme was also the principal catalyst in the main pathways of testosterone and estradiol metabolism in human liver, namely, 613- and 2-hydroxylation, respectively. Further studies in this
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