Influence of oral contraceptives on drug therapy Alexander T. Teichmann, Prof. Dr. med. Gottingen, West Germany Interferences between drugs and oral contraceptives are considered to alter pharmacokinetics and thus the efficacy of steroidal hormones. It should be noted, however, that steroids can also modify the metabolism and pharmakodynamic effects of various substances. To the present knowledge, phase I (Le., oxidation, demethylation) and phase II reactions (conjugation) are concerned. Drugs sharing those enzymatic systems with oral contraceptives experience either an increase in bioavailability by inhibition of oxidative metabolism or undergo accelerated elimination by induced conjugation. Such interaction may be of practical interest in subjects who take oral contraceptives and are simultaneously treated with antidepressants, antihypertensives, insulin, synthetic glucocorticoids, theophylline, and caffeine. (AM J OBSTET GVNECOL 1990;163:2208-13.)

Key words: Oral contraceptives, drug interactions, pharmacokinetics, pharmacodynamics Although oral contraceptives (OC) are among the most widely used drugs in the world whose effects and side effects have been extensively investigated, their pharmacology still remains a perplexing field of multivariate processes. The biochemical and physiologic actions of estrogens and gestagens are not simply additive when given in combination, and their interactions with other drugs lead to an even greater degree of complexity. The following attempt to review the effects of OCs on the pharmacology of other drugs will inevitably be all but satisfactory not only because it is made by a gynecologist but also because a reviewer's task is to condense and stratify information rather than to present all details available. Three major principles of drug interactions exist, of which the chemical reaction between drugs is unlikely to apply to steroid hormones. OCs can, however, influence pharmacokinetics, particularly through protein binding patterns, and metabolism, and they can also interfere with pharmacodynamics. Most commonly interactions of OCs with other drugs will take place if phase I reactions are concerned. It is well known that cytochrome systems P-4S0 and P-448 can be inhibited by OCs either directly or by competition. Moreover, phase II reactions, namely, conjugation with acids, are positively influenced by OCs through enzyme induction. Orally administered ethinyl estradiol (EE) exerts a strong stimulatory effect on protein synthesis, which is partly opposed by gestagens. Finally, receptor-mediated hormonal actions may interfere with wanted or unwanted drug effects of hormonal and non hormonal agents. From the Department of Obstetrics and Gynecology, Georg-AugustUniversitiit Gottingen. Reprint requests: Prof Dr. med. A.T. Teichmann, Univ.Frauenklinik Gottingen, Robert-Koch-Straf3e 40. 3400 Gottingen, West Germany. 6/0/24557

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Before I discuss groups of commonly prescribed pharmaceutical products in detail with respect to the interfering actions of OCs, a few basic remarks are necessary: 1. Combined OCs represent a homogenous group of hormonal agents as far as the type of estrogen and the oral route of administration are concerned. 2. Combined OCs are heterogenous with regard to the doses of EE and the type and dosage of the gestagen. 3. The biologic effects of OCs do not depend solely on their composition and route of administration, but to a large extent depend on individual factors such as age (metabolic activity), individual pharmacokinetics, dietary habits, body mass, physical activity, neuroendocrinologic conditions, and numerous others. These characteristics of OCs and their actions in individual organisms will be largely omitted in the following summary of our knowledge on how OCs modify the effects of other drugs. Although I am quite aware that simplifications may sometimes lead to wrong conclusions, limited space demands this sacrifice for a more pragmatic approach (Table I). Contradictory findings in the following studies cited may be explained by factors such as differences in OC composition and individual conditions. Analgesics belong to the most frequently taken drugs available without medical prescription, and thus it is not remarkable that they are often taken during hormonal contraception. Phenazone is mainly metabolized by oxidation. Its halflife is prolonged, and its clearance rate is reduced by OCs as a result of delayed hydroxylation. Similar conclusions were reached by the authors of other studies investigating the effects of EE on pethidine, a synthetic morphine-analog. Morphine undergoes conjugation with glucaronic acid, and enzy-

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Table I. Influence of OCs on the pharmakinetics of commonly prescribed drugs Bioavailability Type Analgesics

Generic Phenazone Aminophenazone Paracetamol

Aspirin Morphine Ethylmorphine Tranquilizers

Pethidine Alprazolam Trizolam (bromazepam) Chlordiazepoxid Nitrazepam Diazepam

I

Augmented Inhibited oxidation Decreased clearance Increased half-life Inhibited demethylation

Induced conjugation Induced oxidation Increased clearance Induced conjugation Induced conjugation

Inhibited de methylation Inhibited oxidation

Decreased clearance Inhibited oxidation

Increased clearance

Lorazepam Temkzepam Oxazepam Tricyclic antidepressants Antiepileptics

(Increased conjugation)

Imipramine

Decreased clearance

Phenytoin

Inhibited oxidation

Anticoagulants

Coumarin derivatives

Antihypertensives

Metoprolol Oxprenolol Propranolol Clofibrate

Glucocorticoids

Cortisol Prednisolone

Markers

Theophylline Aminophylline Oxitriphylline Coffeine

Inhibited oxidation

Inhibited oxidation

Decreased clearance Decreased clearance (inhibited oxidation)

Inhibited oxidation Inhibited oxidation

matic process that is stimulated by OCs, leading to enhanced metabolism and thus inactivation of this drug. In rat liver preparations, however, as shown by Carter et al.,1 ethylmorphine metabolism is reduced by inhi-

Authors Teunissen et aI., 1982 2R Aberneth y et aI., 1981'" Crawford et aI., 196630 Herz et aI., 1977" Mitchel et aI., 1983 3 Miners et aI., 1983a Miners et aI., 1983 Abernethy et aI., 1982 32 Miners et aI., 1986' Mitchell et aI., 1983b Carter et aI., 1973 1 Herz et aI., 1977 31 Stoehr et aI., 19846 Stoehr et aI., 19846 Ochs et aI., 1987 33 Roberts et aI., 1979 34 Greenblatt et aI., 1977 35 Patwardhan et aI., 1983 36 Jochemsen et al., 1982" Giles et aI., 1981 38 Abernethy et aI., 1982, 1984 10 ,32 Routledge et aI., 1981'9 Greenblatt et aI., 198040 Stoehr et aI., 1984" Patwardhan et aI., 1983 36 Stoehr et aI., 1984 6 Patwardhan et aI., 1983 36 Abernethy et aI., 1983 41 Abernethy et aI., 1984 10 Kutt et aI., 196842 De Leacy et aI., 197943 Hooper et aI., 1974" Tephly and Mannering, 196945 De Teresa et aI., 1979 46 MacLeod and Sellers, 197647 Koch-Weser et aI., 1971 48

Inhibited oxidation

Barbiturates

Lipid-lowering drugs

Decreased

Increased conjugation Increased glucuronidation

Kendall et aI., 198249 Kendall et aI., 198450 Miners et aI., 198451 Marks et aI., 1961 52 Gustavson, 1986 53 Legler and Benet, 1986 54 Shaw et aI., 1983 55 Boekenoogen et aI., 1983 56 Kozower et aI., 197457 Frey et aI., 198458 Frey and Frey, 1985 59 Gardner and Jusko, 1986 16 Roberts et aI., 1983 17 Gardner et aI., 198360 Pathwardhan et aI., 198061 Abernethy et aI., 1985 62 Meyer et aI., 198863

bition of its de methylation in the presence of OCs. The ability ofOCs to induce enzymatic conjugation, namely, with glucuronic and sulfuric acid, seems to be the mode of action by which the metabolism of paracetamol and

2210 Teichmann

aspirin is enhanced. In particular, glucuronidation accounts for 90% of the biotransformation of paracetamol. Because this substance is also metabolized by oxidation, the corresponding influence of OCs on this reaction is of interest. However, the findings reported by Miners et aF and Mitchell et al. 3 are contradictory. It may be of importance to note that Gupta et al! found the influence of OCs on aspirin glucuronidation to decrease with the time of OC use. Morphine shows decreased bioavailability as a result of stimulatory effect on conjugation with glucuronic acid, whereas in rat liver preparation, the demethylation of ethylmorphine seems to be inhibited. Pethidine is negatively influenced in its metabolism by inhibition of oxidation. Whereas numerous reports deal with contraceptive efficacy that is threatened by antibiotics and tuberculostatics, namely, rifampicin, little is known about the effects of OCs on antibiotic treatment. Only in the case of ampicillin were no alterations in plasma levels found in pilltakers between days 21 and 28 of the artificial cycle. Like analgesics, tranquilizers, namely, the benzodiazepine, are among the most frequently used drugs in the Western population. Most of these drugs undergo oxidation, and only a few are metabolized predominantly by conjugation. Analogous to cimethidine, a strong inhibitor of microsomal oxidation, OCs inhibit or at least slow down oxidation and thus lead to a reduction in the clearance rates of the benzodiazepines. Because the activity of microsomal oxidation processes decrease with age and because female sex hormones negatively influence the cytochrome P-4S0 and P-448 systems, both factors diminish clearance rates of the first group of tranquilizers. In contrast, those benzodiazepines that undergo conjugation as their main metabolic pathway experience a higher clearance rate in OC-treated subjects. Other benzodiazepines, such as clotiazepam and triazolam, showed no pharmacologic changes from OCS. 5 ,6 For the practical clinician, the question arises whether and to what extent pharmacokinetic interactions between OCs and benzodiazepines correspond to clinical interactions. A significant delay in psychomotor impairment of OC users compared with nonusers, wllich was observed by Ellinwood et al. 7 did not show any correlation with the plasma levels of diazepam, which had been found to be elevated in women and OC users compared with men. Contrasting findings were reported by Krobath et aI.B for alprazolam, triazolam, and lorazepam. Psychomotor changes were most marked in women who were on the pill. However, again plasma levels did not correlate with the observed clinical effect. Therefore, other hypothetic pharmacodynamic interferences must be postulated, such as a direct change in

December 1990 Am J Obstet Gynecol

membrane properties, to explain the lack of clinical manifestation of pharmacokinetic findings. Tricyclic antidepressants, such as imipramine, clomipramine, and chlorpromazine, were suspected of having increased side effects in OC users on the basis of the observations by Prange. 9 It has been demonstrated that the clearance rate of imipramine is negatively influenced by OCs whereas protein binding and half-life are unaffected. Imipramine is metabolized by demethylation and oxidation before conjugation with glucuronic acid; OCs seem to inhibit oxidation and thus augment bioavailability from 27% to 44%.10-12 In contrast, clomipramine is not influenced by OCs, although its metabolic rate is enhanced by estrogens and inhibited by gestagens, at least in animal models. 13 The psychotropic effects of sex steroids must be added to the pharmacokinetic interferences. Thus it seems wise to monitor the clinical effects of antidepressants thoroughly if they are given to OC users. Antiepileptics of the phenytoin type as well as barbiturates are metabolized by oxidation. In addition to influencing the protein binding of phenytoin, OCs lead to a lower oxidation rate in both groups. Since both estrogens and gestagens interfere with amine metabolism in the brain and are known to augment (estrogens) or lower (gestagens) convulsibility, various pharmacodynamic effects are assumed to overlap the clinical manifestations of altered pharmacokinetics. Indirectly acting anticoagulants, vitamin K antagonists, or coumarin derivatives undergo enzymatic oxidation that is inhibited by cimethidine and induced by phenobarbital. Studies conducted in OC users showed the inhibiting effects of OCs. Moreover, pharmacodynamic interactions may well be of practical importance. Coumarins inhibit the synthesis of vitamin Kdependent coagulation factors VII, IX, and X. Estrogens, namely, orally administered EE, stimulate various coagulation and fibrinolytic agents, in particular factors VII and X, and thus lead to a partial functional antagonism. The net effect of pharmacokinetic and dynamic interferences depends not only on EE dose but also on the type and dose of the gestagen. Because the influence of vitamin K antagonists is the limiting factor in anticoagulatory therapy, OCs clearly weaken their effect. The potency of OCs to induce or exaggerate elevated blood pressure is well known. EE and gestagens, with the exception of progesterone, cause water and sodium retention and act by way of antidiuretic hormone and aldosterone. The predominant influence is that of EE on the synthesis of renin substrate, thus stimulating the renin angiotensin aldosterone system. Other sites of action of estrogens may be in the heart muscle and the vessel wall. Antihypertensive drugs show great het-

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erogenity in their chemical structure and modes of action. Because OCs influences blood pressure regulation, pharmacodynamic interactions are to be expected, particularly if pill-induced forms of hypertension are concerned. ~-Receptor blockers, such as metroprolol, oxpreno101, and propranolol, undergo oxidation that is inhibited by OCs, leading to higher bioavailability. Acebutolol kinetics do not interfere with OCs since this drug undergoes unmetabolized renal elimination. The interaction of an OC with centrally acting antihypertensives such as clonidine may be mediated by (Xadrenergic and dopaminergic receptors. Pharmacokinetic interactions are not known. 14 Clofibrate is commonly used in subjects with hyperlipidemia. Its glucuronidation rates are elevated by OCs, leading to a 48% increase in the clearance rate. Thus the pharmacologic effect of clofibrate is weakened. However, the well-known pharmacodynamic influence of estrogens and gestagens on lipid and lipoprotein metabolism should not be neglected. It largely depends on the type of contraceptive pill and on a great variety of pretherapeutic conditions that have been mentioned above. A general statement that subjects treated for hyperlipidemia should not receive OCs cannot be made at this time on the basis of pharmacokinetic and pharmacodynamic interferences. It is still not clear which OCs have effects on the different forms of hyperlipidemia, what these effects are, and how treatment results are modified by OCs. In contrast to lipid and lipoprotein metabolism, the pharmacodynamic influences of OCs mainly relate to gestagen interference with antidiabetic treatment. Gestagen-induced peripheral insulin resistance may lead in some cases to dose adaptation of insulin. Oral antidiabetic drugs are not likely to be prescribed to juvenile diabetics, which may account for the vast majority of diabetic patients being on the pill. Of the various hormonal treatment regimens, glucocorticoids are among the most frequently prescribed drugs. It is well known that cortisone-binding globulin and the levels of endogenous cortisol are elevated by EE. Since Spangler et al. 15 reported a two-fold to 20fold increase in the antiinflammatory effects of topical hydrocortisone on OC users, it has been established that estrogens may well influence the ratio of free and protein-bound glucocorticoids. The mechanism of estrogen action as described for prednisolone seems not only to act by altered protein-binding patterns between cortisol-binding globulin and albumin but also by an inhibited metabolism of prednisolone, mainly because of reduced microsomal oxidation. No influences on pharmacokinetics have been found for fluocortolone. Substances that are characteristic for specific meta-

Influence of oral contraceptives on drug therapy

2211

bolic processes may be regarded as "markers," in addition to their therapeutic properties. Such markers are theophylline and derivatives, caffeine, and alcohol. Theophylline undergoes oxidation by cytochrome P450 and P-448-dependent systems. Both oxidation and clearance rates are lowered by OCs. Because smoking exerts an enzyme-inductive effect, inhibitory actions of OCs on theophylline metabolism are not observed in smoking subjects who are on the pill. The enzymatic and metabolic link between OC and tobacco action, however, remains uncertain. 16, 17 Caffeine metabolism is mediated by cytochrome P440 oxidation. As with theophylline, the clearance rates for caffeine are negatively influenced by OCs. The findings concerning alcohol and alcohol dehydrogenase activity and interaction with OCs are not clearly defined. Decreased elimination rates are not likely to result from OC-induced cytochrome P-450 inhibition, to which only a minor metabolic fraction is subjected. Clinically relevant conclusions cannot be drawn at this time. 18, 19 OCs exert influences on various vitamins and minerals. Increased plasma levels of iron, copper, and vitamins A, D, and K were found in OC users, whereas concentrations of zinc, folic acid, and vitamins B l , B6, Bl2 and C decreased with the use of estrogens and gestagens!O-27 Whereas in subjects with normal dietary habits these effects will not be clinical relevant, under deprived conditions, reduced plasma levels of essential factors may be of some concern. In conclusion, as noted above, the effects of oral contraceptives on drug therapy are related mainly to the inhibition of microsomal oxidation and demethylation, as well as the induction of enzymes involved in co~ugation reactions. Drugs that share these metabolic pathways will be affected in their pharmacokinetics. However, various pharmacodynamic interferences between OCs and the effects of other drugs may, in most instances, be counterbalanced with kinetic alterations, resulting in a weak or no obvious clinical manifestations. Attention should be paid mainly to a possible modification of the pharmacologic effects in treatment with antidepressants antihypertensives, insulin, synthetic glucocorticoids, theophylline, and caffeine. Even if such interactions may not be present in all subjects, clinical consequences must be drawn, particularly in predisposed persons. REFERENCES 1. Carter DE, GoldmanJM, Bressler R, Huxtable RJ, Christian CD, Heine MW. Effects of oral contraceptives on drug metabolism. Clin Pharmacol Ther 1973;15:22-31. 2. MinersJO, Grgurinovich N, Whitehead AG, Robson RA, Birket DJ. Influence of gender and oral contraceptive

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3.

4.

5. 6.

7.

8. 9. 10. 11. 12. 13. 14.

15.

16. 17. 18. 19. 20. 2!. 22.

23. 24.

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steroids on the metabolism of salicylic acid and acetylsalicylic acid. Br J Clin Pharmacol 1986;22:135-42. Mitchell MC, Hanew T, Meredith CG, Schenker S. Effects of oral contraceptive steroids an acetaminophen metabolism and elimination. Clin Pharmacol Ther 1983;34:4853. Gupta KC,JoshiJV, Hazari K, Pohujani SM, Satoskar RS. Effect of low dose estrogen combination oral contraceptive on metabolism of aspirin and phenylbutazone. Int J Pharmacol Ther Toxicol 1982;20:511-3. Parke DV. Induction of drug metabolising enzymes. In: Parke DV, ed. Enzyme induction. London: Plenum Press, 1984:228. Stoehr GP, Kroboth PD, Juhl RP, Wender DB, Phillips JP, Smith RB. Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics. Clin Pharmacol Ther 1984;36:683-90. Ellinwood EH Jr, Easler ME, Linnoila M, Molter DW, Heatherly DG, Bjornsson TD. Effects of oral contraceptives on diazepam-induced psychomotor impairment. Clin Pharmacol Ther 1984;35:360-6. Kroboth PD, Smith RB, Stoehr GP, Juhl RP. Pharmacodynamic evaluation of the benzodiazepine-oral contraceptive interaction. Clin Pharmacol Ther 1985;38:525-32. Prange AJ. Estrogen may well affect the response to antidepressants. JAMA 1972;219: 143-4. Abernethy DR, Greenblatt DJ, Shader Rl. Imipramine disposition in users of oral contraceptive steroids. Clin Pharmacol Ther 1984;35:792-7. Gringas M, Beaumont G, Grieve A. Clomipramin and oral contraceptives: an interaction study-clinical findings. J Int Med Res 1980;8:76-80. Luscombe DK, John V. Influence of age, cigarette smoking and the oral contraceptive on plasma concentrations of clomipramin. Postgrad Med J 1980;56:99-102. Fletcher HP, Miya TS, Bousquet WF. Influence of estradiol on the disposition of chlorpromazine in the rat. J Pharm Sci 1965;54: 1007-9. Chalmers JS, Fulli-Lemaire J, Cowen PJ. Effects of the contraceptive pill on sedative responses to clonidine and apomorphine in normal women. Psychol Med 1985; 15:63-367. Spangler AS, Antoniadas HN, Sotman SL, Inderbitzin TM. Enhancement of the anti-inflammatory action of hydrocortisone by estrogen. J Clin Endocrinol 1969;29: 650-5. Gardner MJ,Jusko WJ. Effects of oral contraceptives and tobacco use on the metabolic pathways of theophylline. IntJ Pharmacol 1986;33:55-64. Roberts RK, Grice J, McGuffie C, Heilbronn L. Oral contraceptive steroids impair the elimination of theophylline. J Lab Clin Med 1983;101:821-5. Jones MK, Jones MB. Ethanol metabolism in women taking oral contraceptives. Alcohol Clin Exp Res 1984;8:8. Hobbes J, Boutagy J, Shenfield GM. Interactions between ethanol and oral contraceptive steroids. Clin Pharmacol Ther 1985;38:371-80. Webb JL. Nutritional effects of oral contraceptive use. A review. J Reprod Med 1980;25: 150-6. Schenker JG, Jungreis E, Polish uk WZ. Oral contraceptives and correlation between copper and ceruloplasmin levels. IntJ FertilI972;17:28-32. Rhode BM, Cooper BA, Farmer FA. Effect of orange juice, folic acid and oral contraceptives on serum folate in women taking a folate-restricted diet. J Am Coll Nutr 1983;2:221-30. Rivers JM, Devine MM. Plasma ascorbic acid concentrations and oral contraceptives. Am J Clin Nutr 1972; 25:684-9. Luhby AL, Brin M, Gordon M, et al. Vitamin B6 metabolism in users of oral contraceptive agents. 1. Abnormal urinary xanthurenic acid excretion and its correction by pyridoxine. AmJ Clin Nutr 1971;24:684-93.

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25. Aly HE, Donald EA, Simpson MH. Oral contraceptives and vitamin B6 metabolism. AmJ Clin Nutr 1971;24:297303. 26. Heilmann E. Orale Kontrazeptiva und Vita mine. Dtsch Med Wochenschr 1979;104:144-6. 27. Basu TK. Drug and vitamin interactions in adult. Int J Vitamin Nutr Res 1984;54:157-68. 28. Teunissen MWS, Srivastava AK, Breimer DD. Influence of sex and oral contraceptive steroids on antipyrine metabolite formation. Clin Pharmacol Ther 1982;32: 240-6. 29. Abernethy DR, Greenblatt DJ. Impairment of antipyrin metabolism by low-dose oral contraceptive steroids. Clin Pharmacol Ther 1981;29:106-10. 30. CrawfordJS, Rudolfsky S. Some alterations in the pattern of drug metabolism associated with pregnancy, oral contraceptives and the newly born. Br J Aneasth 1966; 38:446-54. 31. Herz R, Koelz HR, Haemmerli MP, Benes J, Blum AL. Inhibition of hepatic de methylation of aminopyrine by oral contraceptive steroids in humans. Eur J Clin Invest 1978;8:27-30. 32. Abernethy DR, Greenblatt DJ, Divoll M, Arendt R, Ochs HR, Shader Rl. Impairment of diazepam metabolism by low-dose estrogen-containing oral contraceptive steroids. N EnglJ Med 1982;306:791-2. 33. Ochs HR, Greenblatt DJ, Friedman H, et al. Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine and propranolol. Clin Pharmacol Ther 1987;41:562-70. 34. Roberts RK, Desmond PV, Wilkinson GR, Schenker S. Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives. Clin Pharmacol Ther 1979; 25:826-31. 35. Greenblatt DJ, Shader RI, Franke K, MacLaughlin DS, Ransil BJ, Koch-Weser J. Kinetics of intravenous chlordiazepoxid: sex differences in drug distribution. Clin Pharmacol Ther 1977;22:893-903. 36. Patwardhan RV, Mitshell MC, Johnson RF, Schenker S. Differential effects of oral contraceptive steroids on the metabolism of benzodiazepines. Hepatology 1983;3:24853. 37. Jochemsen R, van der Graaff M, Boeijinga JK, Breimer DD. Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam. Br J Clin PharmacoI1982;13:319-24. 38. Giles HG, Sellers EM, Naranjo CA, Frecker RC, Greenblatt DJ. Disposition of intravenous diazepam in young men and women. Eur J Clin PharmacoI1981;20:207-13. 39. Routledge PA, Stargel WW, Kitchell BB, Barchowsky A, Shand DG. Sex-related differences in the plasma protein binding of lidocain and diazepam. Br J Clin Pharmacol 1981; II :245-50. 40. Greenblatt DJ, Allen MD, Harmatz JS, Shader R1. Diazepam disposition determinants. Clin Pharmacol Ther 1980;27:301-12. 41. Abernethy DR, Greenblatt DJ, Ochs HR, et al. Lorazepam and oxazepam kinetics in woman on lowdose oral contraceptives. Clin Pharmacol Ther 1983;33:628-32. 42. Kutt H, McDowell F. Management of epilepsy with diphenylhydantoin sodium. JAMA 1968;203:969-72. 43. de Leacy EA, McLeay CD, Eadie MJ, Tyrer JH. Effects of subjects' sex and intake of tobacco, alcohol and oral contraceptives on plasma phenytoin levels. Br J Clin Pharmacol 1979;8:33-6. 44. Hooper WD, Bochner F, Eadie MJ, Tyrer JH. Plasma protein binding of diphenylhydantoin. Effects of sex hormones, renal and hepatic disease. Clin Pharmacol Ther 1974;15:276-82. 45. Tephyly TR, Mannering GJ. Inhibition of drug metabolism by steroids. Med PharmacoI1969;4:10-4. 46. de Teresa E, Vera A, OrtigosaJ, Pulpon LA, Arus AP, de Artaza M. Interaction between anticoagulants and con-

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