Clinical Pharmacokinetics 4; 423-432 0312-5963/79/1100-0423/$02.50/0 © ADIS Press Australasia Pty ltd. All rights reserved.
Hepatic First-pass Metabolism in Liver Disease Terrence F. Blaschke and Peter C. Rubin 1 Division of Clinical Pharmacology, Stanford University Medical Center, Stanford, California
Summary
Many drugs are known or suspected of having substantial first-pass hepatic metabolism in humans, and have low oral bioavailability on this basis. Hepatic disease might alter (increase) bioavailability by either or both of 2 mechanisms: decreased hepatic extraction due to impaired hepatic drug metabolising activity, or portosystemic shunting. Few studies have examined the effect of liver diseases on bioavailability, and even fewer have attempted to directly measure hepatic extraction of drugs in liver disease. Data are conflicting, with some evidence to suggest that hepatocyte function is preserved in moderate cirrhosis, while other evidence suggests a decrease in hepatic metabolic function. Several studies show relative preservation of systemic clearance in the face of substantial increases in bioavailability, suggesting that the hepatic arterial blood supply of the liver is an important determinant of systemic clearance in cirrhotic patients. Increases in bioavailability and decreases in systemic clearance have multiplicative, rather than additive, effects on area under the plasma concentration-time curve after oral administration. Clinically. there are important implications qf these studies. ff differences in response between patients with and without liver disease are seen after equivalent intravenous doses q( a high clearance drug, the differences may befurther accentuated after oral dosing. Delayed toxicity, due to accumulation qf high clearance drugs is more likely to occur because qf the longer haff-life and larger available dose. Physicians should use extra caulion in administering high clearance compounds to patients with liver disease.
Administration of a drug into the gastrointestinal tract provides two possible routes of access to the systemic circulation. In the case of rectal or sublingual administration, absorbed drug passes directly into the systemic venous circulation. However, for
I Current address: Department of Materia Medica. Stobhill General Hospital. Glasgow G21 3UW (Scot/and).
the majority of drugs given orally, absorption occurs across that portion of the gastrointestinal epithelium which is drained by veins forming part of the hepatoportal system. Before reaching the systemic circulation such drugs must pass through the liver and are therefore exposed to enzymes in that organ which metabolise drugs and other foreign compounds. For certain drugs which are susceptible to hepatic degradation, a substantial proportion of the
424
Hepatic First-pass Metabolism in Liver Disease
orally administered dose can be metabolised before ever reaching the site(s) of pharmacological action. When this process occurs, it is referred to as firstpass metaboiism or first-pass effect. Theoretically, any drug which is metabolised by the enzyme systems of the liver undergoes first-pass metabolism. As usually employed, however, the term is applied to those drugs which are substantially removed (e.g. 50 % or more) during their first pass through the liver. A list of the drugs known or suspected to have significant hepatic first-pass metabolism appears in table I. Drugs normally having a large hepatic first-pass effect have several features in common. Their hepatic clearance is high and is affected by conditions, both intrinsic and extrinsic to the liver, which alter hepatic blood flow (Rowland et aI., 1976; Nies et aI., 1976). Differences in bioavailability may be the major source of intersubject variability in steady-state concentrations of drug in blood (Gomeni et aI., 1977; Alvan et aI., 1977). Decreases in hepatic function or portosystemic shunting can increase bioavailability significantly, while having little effect on systemic clearance. The purpose of this review is to outline the theoretical basis for the effect of liver diseases on first-pass metabolism and bioavailability, and to summarise the currently available data in this area.
J. Anatomical and Pathophysiological Considerations Relevant to Hepatic First-pass Metabolism
liver, particularly cardiovascular diseases, may also affect hepatocellular function and hepatic blood flow, but do not usually cause portosystemic shunting.
I . I Disordered Function and Structure of the Liver
1.1.1 Disordered Function Many pathological processes which affect the liver cause an acute decrease in the metabolic function of hepatocytes. If there is continued exposure to certain aetiological agents, the initial acute inflammatory res. ponse can progress to chronic inflammation and cirrhosis, with its characteristic histology of fibrosis and nodules of regenerating hepatic cells. The anabolic and catabolic activities of hepatocytes may be differentially affected by disease processes; unfortunately, unlike renal disease, there are no clinical orc:laboratory tests which provide a quantitative estimate of hepatocyte function. A few tests [e.g. 14C-aminopyrine breath tests, sulphobromophthalein (BSP) or indocyanine green (lCG) clearances] have been shown to correlate with the hepatic clearances of a few selected drugs in vivo (Hepner, 1978; Wood et aI., 1978). They have also served to confirm the heterogeneic effects which a similar disease process may have on the metabolism of a specific drug in a group of patients. Nevertheless, if any disease produces an acute or chronic decrease in the ability of the liver to metabolise drugs, a change in first-pass metabolism would be expected.
1.1.2 Portal-systemic Venous Shunting There are 2 major determinants of the extent of The disordered liver architecture seen in cirrhosis first-pass metabolism of a drug, which may change alone or in combination. The first is hepatocellular leads to an increased resistance in the hepatic vascular function, and the second is intra- and extrahepatic . bed with consequent portal venous hypertension. As portosystemic shunting. In acute inflammatory liver the result of this increased pressure, portal blood disease the major alteration is in hepatocellular func- passes through extrahepatic and intrahepatic coltion, while in mild-to-moderate cirrhosis the major laterals directly into the systemic venous system. abnormality is in hepatic blood flow and porto- 60 % or even more of portal flow can be diverted systemic shunting. There is often a combination of from functioning hepatocytes in this way (Grozmann both in severe inflammatory liver disease and severe et al., 1972). Such portosystemic shunting might also cirrhosis (Blaschke, 1977). Disorders extrinsic to the be deliberately established in the surgical correction of
425
Hepatic First-pass Metabolism in Uver Disease
portal hypertension. Under these conditions a major proportion of drug absorbed from the gastrointestinal tract will not even be exposed to the metabolic systems of the liver (Gugler et ai., 1975).
1.1.3 Extrahepatic Factors Influencing Absorption and Blood Flow Even when the liver is not the site of primary pathology, diseases involving other organ systems may influence bioavailability and first-pass metabolism. For example, the haemodynamic and metabolic changes accompanying congestive heart failure alter the absorption of several cardiovascular drugs (Benowitz and Meister, 1976). Diseases or other physiological processes (e.g. fever, posture, drugs, food intake) which affect hepatic blood flow can change the systemic clearance of drugs with flow dependent hepatic clearance, but would not be expected to significantly influence bioavailability. However, diseases which increase or decrease hepatic microsomal activity can substantially alter first-pass effect, although they might theoretically be expected to have little influence on the systemic clearance of flow dependent compounds (see Nies et ai., 1976). The effect of extrahepatic factors on hepatic drug clearance and first-pass metabolism can be complex. Phenobarbitone increases both hepatic mass, hepatic blood flow, and intrinsic activity of the microsomal enzyme system (Branch et ai., 1974). Esquivel et ai. (J 978) showed that, in the dog, phenobarbitone increases blood flow and liver weight, but that the microsomal activity per gram of liver was essentially unchanged; the net effect in vivo was a change in the hepatic clearance of both flow dependent and capacity limited drugs, with no change in oral availability (see Nies et ai., 1976 for a discussion of flow dependent and capacity limited drugs and intrinsic clearance). Pulmonary disease has been shown to alter hepatic metabolism of drugs: acute hypoxaemia decreases intrinsic hepatic clearance, while chronic hypoxaemia can increase intrinsic clearance, and alter drug binding to plasma proteins (du Souich et ai., 1978). These alterations in intrinsic clearance would be expected to change the extent of absorption of drugs subject to a
large first -pass effect, but there are no data to confirm this at present. Renal insufficiency also has variable effects on hepatic drug clearance; most reports show that hepatic metabolic activity is unchanged (Reidenberg, 1974), but both decreases and increases in hepatic metabolism have been demonstrated for specific drugs. In one study in which the hepatic extraction and bioavailability of pindolol was directly measured in patients with impaired renal function, hepatic extraction and hepatic clearance were unchanged, but the oral bioavailability was reduced by 40 %, presumably because of effects on the gastrointestinal tract, and not the liver (Lavene et ai., 1977).
1.2 Importance of Dual Hepatic Blood Supply When hepatic anatomy is norma!, the extent of first-pass metabolism and bioavailability (F) can often be predicted if the hepatic clearance is known. This derives from the following well known relationship: CIH
F = 1- - EHBF
(Eq. I)
where EHBF is the effective hepatic blood flow (often estimated at about 1.5L/min in normal adults), CIH is the hepatic clearance, and F is the bioavailability. The term CIH/EHBF is equivalent to the hepatic extraction ratio (ER) for the drug and can be rearranged as follows: CIH = (EHBF)· (ER)
(Eq.2)
Equations 1 and 2 assume that the hepatic clearance is linear (e.g. is not saturated at high concentrations) and- that there is mixing of blood from the hepatic artery and portal vein in the hepatic sinusoids. Equation 1 is valid only when absorption from the gastrointestinal tract is complete. In diseases which cause portosystemic shunts, the assumption that there is mixing of portal and hepatic arterial blood is not valid, and bioavailability may be underestimated from measurements of hepatic clearance (Neal et al., 1979). This is probably a consequence of the dual blood supply of the liver. Drug which is ad-
Hepatic First-pass Metabolism in Liver Disease
426
ministered orally enters only the portal venous system after crossing the gut mucosa, and its bioavaiIability is dependent on the fraction of portal flow which is shunted and the hepatic extraction ratio: F
=
CIH SF + (I - SF) x (I - - - ) EHBF
measured systemic clearance (see below) is a consequence of the dual blood supply (Laut, 1977).
1.3 Dose-dependent First-pass Metabolism (Eq. 3)
where SF is the fraction of portal venous flow which is shunted to the systemic venous system, and EHBF is the effective hepatic blood flow, consisting of the hepatic arterial flow and the non-shunted portal venous flow. In this equation, the term CIH/EHBF again represents the hepatic extraction ratio. Comparing equation 3 with equation I, several differences can be seen. In equation 3 an important determinant of bioavailability is the shunt fraction (SF); as SF approaches unity, the bioavailability approaches I and the EHBF approaches the value for hepatic arterial flow. Since hepatic arterial flow (representing approximately one third of splanchnic blood flow in normal subjects) is usually maintained and may even be increased in cirrhotic patients, hepatic clearance, physiologically determined as the product of EHBF and ER (equation 2), may remain relatively large, if hepatocyte function does not substantially deteriorate. Figure I illustrates the relationships between portosystemic shunting, clearance and bioavailability for drugs with moderate (0.5) and high (0.8) hepatic extraction ratios. The theoretical values for clearance and bioavailability are calculated from equation 3 and are based on the assumptions that hepatic arterial flow is maintained, and that the hepatic extraction ratio is unchanged. The latter assumption mayor may not be valid; indirect measurements in cirrhotics using model compounds suggest that intrinsic clearance is relatively unaffected. However, a recent direct measurement of d-propranolol hepatic extraction in cirrhosis demonstrates a substantial (44 %) fall mextraction and an even more dramatic decrease in calculated intrinsic hepatic clearance (Pessayre et aI., 1978). Nevertheless, it is likely that some of the differences between observed bioavailability and that which would be predicted on the basis of the
For drugs which have linear kinetics, the concentrations in blood or plasma are proportional to the size of the oral dose, and bioavailability is independent of dose. However, a few drugs seem to show dose dependent bioavailabiIity including: salicylamide (Barr et aI., 1973); chlormethiazole (Jostell et aI., 1978) and 5-fluorouracil (Christophidis et aI., 1978). Data are controversial concerning dose-dependent absorption of propranolol. Shand and Rangno (I 972) observed that a threshold dose of approximately 30mg of propranolol was needed before plasma levels could be observed after a single oral dose. Gomeni et al. (I 977), using different analytical methodology, were unable to confirm this nonlinearity, although they found a longer half-life after low dose (I Omg) oral administration. Subsequent investigations suggest that a threshold may indeed be present, but at lower doses than originally observed (see Routledge and Shand, 1979). Mechanisms responsible for dose dependent availability are unknown. There is a lack of solid experimental data regarding the hepatoportal concentrations of drugs after oral or intravenous administration. Depending on the rate of absorption, volume of distribution and rate of distribution from plasma to tissues, it is possible to achieve significantly higher hepatoportal concentrations after oral administration than are seen after intravenous doses (Rowland, 1973). Under such circumstances, 'saturation' of first-pass metabolism is possible. Differences in patterns of metabolites have been reported after the oral versus intravenous administration of propranolol (Paterson et aI., 1970) and hydrallazine (Talseth, 1977), which are consistent with saturation of hepatic enzyme systems, or intestinal mucosal first-pass effects. It is perhaps surprising how few drugs demonstrate dose dependent bioavailability; it is uncertain, however, whether saturable first-pass metabol-
427
Hepatic First-pass Metabolism in Uver Disease
ism is more likely under conditions of hepatic dysfunction. Such a mechanism is consistent with observations regarding bioavailability and systemic clearance which will be presented in the next section.
2. The Influence of Hepatic Dysfunction on First-pass Metabolism of Specific Drugs Quantitative assessment of first-pass metabolism requires the comparison of data obtained after intravenous administration of a drug with that resulting from oral administration. A drug given intravenously has 100 % bioavailability, and, assuming linear kinetics, the area under the resulting blood (or plasma) concentration-time curve extrapolated to infinity (AUC iy]'0) serves as a reference value against which to compare the area following oral administration (AUCo1 0>. Bioavailability is then simply defined as:
there are very few studies which have measured bioavailability and estimated first-pass metabolism in patients with liver disease. The drugs for which such information is available are: chlormethiazole, labetalol, lignocaine (lidocaine), paracetamol (acetaminophen), pentazocine, pethidine (meperidine), and propranolol.
2.1 Chlormethiazole (Pentikainen et aI., 1978)
Chlormethiazole, a sedative/hypnotic agent, was studied in 8 men with biopsy proven cirrhosis and 6 age matched healthy male volunteers. Each subject received orally 192mg of chlormethiazole base and, on another occasion, an equimolar dose given intravenously. Blood samples were collected for at least 5 elimination half-lives and chlormethiazole concentrations measured by mass fragmentography. The bioavailability of chlormethiazole in the control subjects compared with the cirrhotic subjects was AUCo] ~/Dosea F (Eq.4) 11.8 ± 2.9% versus 136 ± II %, respectively. The AUCjy] ~/Dos~y latter figure, indicating an oral bioavailability of greater than 100 % , is probably methodological, since Of course, if the value for F is less than one, it is not the concentrations after oral and intravenous adnecessarily the result of first-pass hepatic metabolism. ministration to the cirrhotic subjects were similar. Low bioavailability following oral administration Other sources of nonlinearity, such as hepatic uptake could result from poor absorption, from metabolism or distribution, might also explain these results. by micro-organisms in the alimentary tract (RowOf interest is the observation that, although there land, 1973) or from metabolism in the gut wall, as was an II-fold increase in bioavailability, the sysdemonstrated for chlorpromazine and L-dopa temic clearance after intravenous administration is (Gibaldi and Perrier, 1974). However, strong indica- only modestly reduced, from 18.1 ± 1.2ml/min/kg tions that first-pass metabolism is responsible for an in normals to 12.8 ± 1.7ml/min/kg in the cirrhotic observed low bioavailability following oral ad- patients, a fall of 30 %. As discussed earlier, this 'disministration is a high nonrenal systemic clearance crepancy' between systemic clearance and bioavailafter intravenous administration. Unfortunately, in- ability may be related to the dual blood supply, or to travenous data are not always available, for a variety saturation of hepatic enzymes in the cirrhotic patient of reasons. When only data after oral administration after oral, but I,lot intravenous administration. can be obtained, a short half-life and extensive meta- Because of the similarity in concentrations after either bolism is suggestive evidence for substantial first-pass the oral or intravenous route, the latter possibility metabolism. seems less likely and, even if it occurred, could not acAlthough there are an increasing number of count for the bioavailability value of greater than reports in the literature describing the influence of 100 %. Another finding, of some clinical relevance hepatic dysfunction on systemic clearance of drugs, (as will be discussed later) is the finding that the area
428
Hepatic First-pass Metabolism in Liver Disease
under the plasma concentration-time curve after oral administration (AUCeJ Q) is increased by a factor of 17 in the cirrhotic patient, compared with the II-fold increase in bioavailability.
2.2 Labetalol (Homeida et ai., 1978) The disposition of this relatively new hypotensive agent, a combined a- and ~-adrenoceptor blocking drug, was compared in 10 patients with histologically proven cirrhosis and 7 normal control subjects. The controls were aged 22 to 42 years while the mean age of the patients was 57.7 years. After both oral and intravenous administration of the drug, plasma samples were collected for 2 half-lives and labetalol was analysed by spectrofluorometry. The sensitivity and accuracy of the method are not stated. In normal subjects, labetalol had a bioavailability of 33 ± 3 %. In the cirrhotic patients bioavailability was 63 ± 7 %. The authors do not discuss systemic clearance, but it can be calculated from their values for AUCiv] '0 and dose. In normal subjects, the clearance is calculated as 2.8L/min, while in the cirrhotics it is 2.0L/min. In view of the figure for bioavailability in normal subjects, and the fact that the clearance in normals exceeds estimated hepatic plasma flow, there is some inconsistency in these data. Renal clearance is apparently not an explanation, since less than 5 % of labetalol is excreted in the urine as unchanged drug. Although there may be some question about the absolute values for clearance, the maintenance of a relatively high systemic clearance in the face of a 2fold increase in bioavailability is again present in this study.
2.3 Lignocaine (Tschang et ai., 1977) Lignocaine (IOOmg IV and 200mg PO) and antipyrine (I Omg / kg) were administered intravenously and orally to 3 healthy controls, 6 cirrhotics with evidence of portal hypertension, and 3 patients with alcoholic hepatitis. The bioavaiiabiJity of lignocaine in
the normal volunteers was 0.33, compared with 0.65 in the cirrhotics and 0.49 in the patients with alcoholic hepatitis. The clearance was decreased from 10.07 ± Iml/min/kg in normals to 5.82 ± 1.3 in the cirrhotic subjects. Values for antipyrine bioavailability are not presented. Lignocaine is usually not given oral1y for therapeutic purposes, but, like antipyrine, has been used as a model compound to study the influence of hepatic blood flow and enzyme activity on drug clearance and first-pass effect.
2.4 Paracetamol (Arnman and Olsson, 1978) Studies were performed in I 5 patients without liver disease, 2 I patients with cirrhosis and 4 patients with secondary liver cancer. Only oral paracetamol was investigated, data being presented on samples drawn for 6 hours. The AUCeJ '0 was 50% above control values both in the cirrhotics and in the patients with metastatic liver cancer, and there was a tendency for patients with portocaval shunts to have even larger values. However, since the relative contribution of decreased clearance versus increased bioavailability cannot be estimated without intravenous dosing, this study permits no conclusions to be drawn concerning paracetamol first-pass effect.
2.5 Pentazocine (Neal et aI., 1979) This study involved 8 patients with biopsy proven cirrhosis and 4 age matched subjects. Pentazocine was given to all study participants in oral and intravenous forms and blood samples obtained for 24 hours following drug administration. Pentazocine was analysed by gas-liquid chromatography with electron capture detection. In the cirrhotic patients, the bioavailabiJity of pentazocine was substantially increased: 0.68 ± 0.21 compared with 0.18 ± 0.05 in the control group. The blood clearance of pentazocine was substantially reduced in the patients: 675 ± 296ml/min com-
429
Hepatic First-pass Metabolism in Uver Disease
pared with 1246 ± 236ml/min for the normal subjects. It is noteworthy that the combined effect of increased bioavailability and decreased blood clearance on the AUCol 0 was multiplicative, not additive and that systemic clearance decreased by less than 50 % in the presence of a greater than 3-fold increase in bio'availability.
2.6 Pethidine (Neal et ai., 1979) The study involved the same subjects as described above for pentazocine and blood sampling was again performed over a 24-hour period. Pethidine was analysed by gas-liquid chromatography with flame ionisation detection. In the cirrhotic patients bioavailability was increased from the normal value of 0.48 ± 0.13 to 0.87 ± 0.27, and blood clearance was reduced from 900 ± 316 to 573 ± 158m1/min. Again the total effect of these changes on AUCol ~ was multiplicative, and the systemic blood clearance in cirrhosis predicts a lower bioavailability than actually observed in the study.
3. Predicting Increased Bioavailability in Patients with Hepatic Dysfunction For the practising physician it is important to predict which drugs in which patients are likely to show substantial changes in bioavailability as the result of liver disease. Few data are available on this subject, but it is apparent that both the pharmacokinetic characteristics of the drug and the type of liver disease will be important determinants of whether increases in bioavaiiabiIity will be seen.
3. I Properties of the Drug In the study of pentazocine and pethidine bioavailability in cirrhotic patients (Neal et ai., 1979),
1
1.0
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~()~, ' ~;; ¥ '/
u '2 J:: u
2.7 Propranolol (Branch et ai., 1977)
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~ ..... ()'O"
!I c:
,-?
"
jects.
0.8 Cl
.5 c:
0.6 ~.g Q)..!!! ~
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0.4
c:
The disposition of propranolol has been studied in 15 normal subjects and 6 patients with cirrhosis. They administered unlabelled drug orally and tritiated propranolol intravenously which is a useful technique for measuring bioavailability that reduces intrapatient variation due to time-dependent changes in clearance. In the normals, propranolol bioavailability was 0.36 ± 0.024 and in the cirrhotics it was 0.60 ± 0.08. Systemic clearance was 898ml/min in normals, compared with 558ml/min in the cirrhotic subjects. In this study there is good agreement between the extent of increase in bioavailability and the decrease in clearance. In a follow up to this preliminary report, Wood et ai. (1978) showed a correlation between antipyrine and indocyanine green clearances and the clearance of propranolol in the cirrhotic sub-
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Percentage shunting of portal venous flow
Fig. 7. Relationship between portosystemic shunting. clearance. and bioavailability. The horizontal axis indicates the percentage of portal blood flow which bypasses the liver. Normals would have no shunting. severe cirrhotics might have 100% shunting. The left hand vertical scale and· solid line shows the systemic clearance (as a fraction of total splanchnic flow) for moderate (ER = 0.5) and high (ER = 0.8) extraction ratio drugs as the percent shunting of portal flow increases. The right hand vertical scale and dashed line shows the corresponding bioavailability values for various degrees of shunting. See text for assumptions and discussion.
Hepatic First-pass Metabolism in Liver Disease
it was found that there was a considerably larger change in pentazocine bioavailability (278 %) than in pethidine bioavailability (81 %). In normal subjects, pentazocine had a much lower bioavailability (0.18) than did pethidine (0.48). If, as seems likely, the findings with these 2 drugs are generally applicable then those drugs with the largest hepatic extraction ratios under normal conditions have the greatest potential for relative increases in bioavailability in patients with hepatic disease. This is consistent with equations I and 3, which show that the shunt fraction (SF) replaces the hepatic extraction ratio as the most important determinant of bioavailability. Figure I also illustrates this same point, with the slope of the increase in bioavailability being steeper for the high extraction ratio drug as compared with the drug with a smaller extraction ratio.
3.2 Characteristics of the Patient No studies have been reported which attempt to correlate patient characteristics with changes in bioavailability. However, in studying the systemic clearance of propranolol (Branch and Shand, 1976), the greatest changes were found in cirrhotic patients with low serum albumin concentrations, raised serum bilirubin and prolonged prothrombin times. Little correlation was found with other tests of liver function. These authors make the point, however, that correlations are likely to be dependent on the type of liver disease and that liver enzymes such as SGPT might serve a useful predicting role in, for example, acute viral hepatitis. It should be emphasised that correlations found to be relevant with regard to systemic clearance will not necessarily be applicable to presystemic metabolism. Several of the studies discussed above have shown that increases in bioavailability may be larger than would be predicted by the observed changes in systemic clearance; a possible explanation for this has been discussed earlier. Clinically, the quantitative estimation of portosystemic shunting is difficult, and none of the readily available laboratory or radiological tests provide
430
Table I. Drugs known or suspected to have high hepatic first-pass metabolism
Acety!salicylic acid Alprenolol Chlormethiazole Chlorpromazine Isoprenaline Labetalol Lignocaine (lidocaine) Methylphenidate Metoprolol Morphine
Nitroglycerine Nortriptyline Paracetamol Pentazocine Pethidine (meperidine) Prazosin Propoxyphene Propranolol Salicylamide
useful quantitative information. It is clear from those studies which have included patients with surgically created portocaval shunts, that such patients have generally higher bioavailability and lower clearance, although the mechanism is unclear and may be related to decreased hepatocyte function in addition to increased shunting.
4. Clinical Implications The clinical relevance of changes in bioavailability due to hepatic disease is clear, even though the number of experimental studies is small. If drugs normally undergo substantial hepatic first-pass metabolism (e.g. those drugs listed in table I), large increases in bioavailability and decreases in systemic blood clearance are to be expected. When such drugs are administered orally, the increase in bioavailability and decrease in clearance will have a multiplicative effect on the total area under the blood concentrati0n-time profile. This means that a SO % decrease in clearance, and a 4-fold increase in bioavailability results in an 8fold increase in the AUCol '0 in cirrhotic subjects, as we have shown with pentazocine (Neal et aI., 1979). If there is a linear proportionality between concentration and response, then the effect on response will also be multiplicative. Thus, any differences in the intensity andlor duration of response observed between controls and patients with liver disease when an
Hepatic First-pass Metabolism in Uver Disease
equivalent dose of a high clearance compound (table I) is given intravenously, will be further accentuated by oral administration. Finally, in patients without liver disease there is ordinarily little accumulation of those high clearance drugs which have short half-lives. In cirrhotic patients who have decreased systemic clearances and longer half-lives, clinically significant accumulation of these drugs may occur in multiple dose regimens, resulting in toxicity which appears after several doses, but not with the first dose. Physicians who use drugs with high first-pass metabolism in cirrhotic patients, or in patients with other conditions where hepatic flow or function may be impaired (Benowitz and Meister, 1976; Jaillon et aI., 1979) should be aware of the necessity to reduce the dose and increase the dosing interval to avoid excessive concentrations of drug.
Acknowledgements Supported in part by National Institutes of Health Grant GM22209. Terrence F. Blaschke is a Burroughs Wellcome Scholar in Clinical Pharmacology, and the recipient of a Research Career Development Award (GM00407) from the NIH. Peter C. Rubin is the recipient of a Research Fellowship from the American Heart Association. We wish to thank Kathleen Giacomini for critical review and Linda Halloran for preparation of the manuscript.
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drawal manifestations. Clinical Pharmacology and Therapeutics 23: 181-187 (1978). Laut. W.W.: The hepatic artery: subservient to hepatic metabolism or guardian of normal hepatic clearance rates of humoral substances. General Pharmacology 8: 73-78 (J 977). Lavene. D.; Weiss. Y.A.; Safar. M.E.; Loria. Y.; Agorus. N.; Georges. D. and Milliez. P.L.: Pharmacokinetics and hepatic extraction ratio of pindolol in hypertensive patients with normal and impaired renal function. Journal of Clinical Pharmacology 17: 501-508 (1977). Neal. E.A.; Meffm. PJ.; Gregory. P.B. and Blaschke. T.F.: Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 77: 96-102 (\ 979). Nies. A.S.; Shand. D.G. and Wilkinson. G.R.: Altered hepatic blood flow and drug disposition. Clinical Pharmacokinetics I: 135-155 (1976). Paterson. J.W.; Dollery. C.T.; Conolly. M.E.; Hayes. A. and Cooper. R.G.: Pharmacodynamics and metabolism of propranolol in man. European Journal of Clinical Pharmacology 2: 217 (1970). Pentikainen. PJ.; Neuvonen. PJ.; Tarpida. S. and Syvalakti. E.: Effect of cirrhosis of the liver on the pharmacokinetics of chlormethiazole. British Medical Journal 2: 861-863 () 978). Pessayre. D.; Lebrec. D.; Descatoire. V.; Peignoud. M. and Benhemou. J.P.: Mechanism for reduced drug clearance in patients with cirrhosis. Gastroenterology 74: 566-571 (\ 978). Reidenberg. M.: Kidney disease and drug metabolism. Medical Clinics of North America 58: 1059-1062 (1974).
Routledge. P.A. and Shand. O.A.: Clinical pharmacokinetics of propranolol. Clinical Pharmacokinetics 4: 73-90 (J 979). Rowland. M.: Effect of some physiological factors on bioavailability of oral dosage forms; LIl Swarbrick tEd) Current Concepts in Pharmaceutical Science: Biopharmaceutics. pp.181-230 (M. Dekker. Inc .• New York 1973). Rowland. M.; Blaschke. T.F.; Meffin. PJ. and Williams. R.L.: Pharmacokinetics in disease states modifying hepatic and metabolic function; in ~enet (Ed) The Effect of Disease States on Drug Pharmacokinetics (American Pharmaceutical Association. Washington 1976). Shand. D.G. and Rangno. R.E.: The disposition of propranolol. Pharmacology 7: 159-168 (J972). Talseth. T.: Clinical pharmacokinetics of hydrallazine. Clinical Pharmacokinetics 2: 317-329 () 977). Tschang. c.; Steiner. l.A.; Hignite. C.E.; Huffman. D.H. and Azarnoff. D.L.: Systemic availability of lidocaine in patients with liver disease (Abstract>. Clinical Research 25: 609A () 977).
Wood. AJ.l.; Kornhauser. D.M.; Wilkinson. G.R.; Shand. D.G. and Branch. R.A.: The influence of cirrhosis on steady-state blood concentrations of unbound propranolol after oral administration. Clinical Pharmacokinetics 3: 478-487 (1978).
Author's address: Prof. Terrence F. Blaschke. Division of Clinieal Pharmacology. Room S155. Stanford University Medical Center. Stanford. CA 94305 (USA).
Hepatic First-pass Metabolism in Liver Disease Terrence F. Blaschke and Peter C. Rubin 1 Division of Clinical Pharmacology, Stanford University Medical Center, Stanford, California
Summary
Many drugs are known or suspected of having substantial first-pass hepatic metabolism in humans, and have low oral bioavailability on this basis. Hepatic disease might alter (increase) bioavailability by either or both of 2 mechanisms: decreased hepatic extraction due to impaired hepatic drug metabolising activity, or portosystemic shunting. Few studies have examined the effect of liver diseases on bioavailability, and even fewer have attempted to directly measure hepatic extraction of drugs in liver disease. Data are conflicting, with some evidence to suggest that hepatocyte function is preserved in moderate cirrhosis, while other evidence suggests a decrease in hepatic metabolic function. Several studies show relative preservation of systemic clearance in the face of substantial increases in bioavailability, suggesting that the hepatic arterial blood supply of the liver is an important determinant of systemic clearance in cirrhotic patients. Increases in bioavailability and decreases in systemic clearance have multiplicative, rather than additive, effects on area under the plasma concentration-time curve after oral administration. Clinically. there are important implications qf these studies. ff differences in response between patients with and without liver disease are seen after equivalent intravenous doses q( a high clearance drug, the differences may befurther accentuated after oral dosing. Delayed toxicity, due to accumulation qf high clearance drugs is more likely to occur because qf the longer haff-life and larger available dose. Physicians should use extra caulion in administering high clearance compounds to patients with liver disease.
Administration of a drug into the gastrointestinal tract provides two possible routes of access to the systemic circulation. In the case of rectal or sublingual administration, absorbed drug passes directly into the systemic venous circulation. However, for
I Current address: Department of Materia Medica. Stobhill General Hospital. Glasgow G21 3UW (Scot/and).
the majority of drugs given orally, absorption occurs across that portion of the gastrointestinal epithelium which is drained by veins forming part of the hepatoportal system. Before reaching the systemic circulation such drugs must pass through the liver and are therefore exposed to enzymes in that organ which metabolise drugs and other foreign compounds. For certain drugs which are susceptible to hepatic degradation, a substantial proportion of the
424
Hepatic First-pass Metabolism in Liver Disease
orally administered dose can be metabolised before ever reaching the site(s) of pharmacological action. When this process occurs, it is referred to as firstpass metaboiism or first-pass effect. Theoretically, any drug which is metabolised by the enzyme systems of the liver undergoes first-pass metabolism. As usually employed, however, the term is applied to those drugs which are substantially removed (e.g. 50 % or more) during their first pass through the liver. A list of the drugs known or suspected to have significant hepatic first-pass metabolism appears in table I. Drugs normally having a large hepatic first-pass effect have several features in common. Their hepatic clearance is high and is affected by conditions, both intrinsic and extrinsic to the liver, which alter hepatic blood flow (Rowland et aI., 1976; Nies et aI., 1976). Differences in bioavailability may be the major source of intersubject variability in steady-state concentrations of drug in blood (Gomeni et aI., 1977; Alvan et aI., 1977). Decreases in hepatic function or portosystemic shunting can increase bioavailability significantly, while having little effect on systemic clearance. The purpose of this review is to outline the theoretical basis for the effect of liver diseases on first-pass metabolism and bioavailability, and to summarise the currently available data in this area.
J. Anatomical and Pathophysiological Considerations Relevant to Hepatic First-pass Metabolism
liver, particularly cardiovascular diseases, may also affect hepatocellular function and hepatic blood flow, but do not usually cause portosystemic shunting.
I . I Disordered Function and Structure of the Liver
1.1.1 Disordered Function Many pathological processes which affect the liver cause an acute decrease in the metabolic function of hepatocytes. If there is continued exposure to certain aetiological agents, the initial acute inflammatory res. ponse can progress to chronic inflammation and cirrhosis, with its characteristic histology of fibrosis and nodules of regenerating hepatic cells. The anabolic and catabolic activities of hepatocytes may be differentially affected by disease processes; unfortunately, unlike renal disease, there are no clinical orc:laboratory tests which provide a quantitative estimate of hepatocyte function. A few tests [e.g. 14C-aminopyrine breath tests, sulphobromophthalein (BSP) or indocyanine green (lCG) clearances] have been shown to correlate with the hepatic clearances of a few selected drugs in vivo (Hepner, 1978; Wood et aI., 1978). They have also served to confirm the heterogeneic effects which a similar disease process may have on the metabolism of a specific drug in a group of patients. Nevertheless, if any disease produces an acute or chronic decrease in the ability of the liver to metabolise drugs, a change in first-pass metabolism would be expected.
1.1.2 Portal-systemic Venous Shunting There are 2 major determinants of the extent of The disordered liver architecture seen in cirrhosis first-pass metabolism of a drug, which may change alone or in combination. The first is hepatocellular leads to an increased resistance in the hepatic vascular function, and the second is intra- and extrahepatic . bed with consequent portal venous hypertension. As portosystemic shunting. In acute inflammatory liver the result of this increased pressure, portal blood disease the major alteration is in hepatocellular func- passes through extrahepatic and intrahepatic coltion, while in mild-to-moderate cirrhosis the major laterals directly into the systemic venous system. abnormality is in hepatic blood flow and porto- 60 % or even more of portal flow can be diverted systemic shunting. There is often a combination of from functioning hepatocytes in this way (Grozmann both in severe inflammatory liver disease and severe et al., 1972). Such portosystemic shunting might also cirrhosis (Blaschke, 1977). Disorders extrinsic to the be deliberately established in the surgical correction of
425
Hepatic First-pass Metabolism in Uver Disease
portal hypertension. Under these conditions a major proportion of drug absorbed from the gastrointestinal tract will not even be exposed to the metabolic systems of the liver (Gugler et ai., 1975).
1.1.3 Extrahepatic Factors Influencing Absorption and Blood Flow Even when the liver is not the site of primary pathology, diseases involving other organ systems may influence bioavailability and first-pass metabolism. For example, the haemodynamic and metabolic changes accompanying congestive heart failure alter the absorption of several cardiovascular drugs (Benowitz and Meister, 1976). Diseases or other physiological processes (e.g. fever, posture, drugs, food intake) which affect hepatic blood flow can change the systemic clearance of drugs with flow dependent hepatic clearance, but would not be expected to significantly influence bioavailability. However, diseases which increase or decrease hepatic microsomal activity can substantially alter first-pass effect, although they might theoretically be expected to have little influence on the systemic clearance of flow dependent compounds (see Nies et ai., 1976). The effect of extrahepatic factors on hepatic drug clearance and first-pass metabolism can be complex. Phenobarbitone increases both hepatic mass, hepatic blood flow, and intrinsic activity of the microsomal enzyme system (Branch et ai., 1974). Esquivel et ai. (J 978) showed that, in the dog, phenobarbitone increases blood flow and liver weight, but that the microsomal activity per gram of liver was essentially unchanged; the net effect in vivo was a change in the hepatic clearance of both flow dependent and capacity limited drugs, with no change in oral availability (see Nies et ai., 1976 for a discussion of flow dependent and capacity limited drugs and intrinsic clearance). Pulmonary disease has been shown to alter hepatic metabolism of drugs: acute hypoxaemia decreases intrinsic hepatic clearance, while chronic hypoxaemia can increase intrinsic clearance, and alter drug binding to plasma proteins (du Souich et ai., 1978). These alterations in intrinsic clearance would be expected to change the extent of absorption of drugs subject to a
large first -pass effect, but there are no data to confirm this at present. Renal insufficiency also has variable effects on hepatic drug clearance; most reports show that hepatic metabolic activity is unchanged (Reidenberg, 1974), but both decreases and increases in hepatic metabolism have been demonstrated for specific drugs. In one study in which the hepatic extraction and bioavailability of pindolol was directly measured in patients with impaired renal function, hepatic extraction and hepatic clearance were unchanged, but the oral bioavailability was reduced by 40 %, presumably because of effects on the gastrointestinal tract, and not the liver (Lavene et ai., 1977).
1.2 Importance of Dual Hepatic Blood Supply When hepatic anatomy is norma!, the extent of first-pass metabolism and bioavailability (F) can often be predicted if the hepatic clearance is known. This derives from the following well known relationship: CIH
F = 1- - EHBF
(Eq. I)
where EHBF is the effective hepatic blood flow (often estimated at about 1.5L/min in normal adults), CIH is the hepatic clearance, and F is the bioavailability. The term CIH/EHBF is equivalent to the hepatic extraction ratio (ER) for the drug and can be rearranged as follows: CIH = (EHBF)· (ER)
(Eq.2)
Equations 1 and 2 assume that the hepatic clearance is linear (e.g. is not saturated at high concentrations) and- that there is mixing of blood from the hepatic artery and portal vein in the hepatic sinusoids. Equation 1 is valid only when absorption from the gastrointestinal tract is complete. In diseases which cause portosystemic shunts, the assumption that there is mixing of portal and hepatic arterial blood is not valid, and bioavailability may be underestimated from measurements of hepatic clearance (Neal et al., 1979). This is probably a consequence of the dual blood supply of the liver. Drug which is ad-
Hepatic First-pass Metabolism in Liver Disease
426
ministered orally enters only the portal venous system after crossing the gut mucosa, and its bioavaiIability is dependent on the fraction of portal flow which is shunted and the hepatic extraction ratio: F
=
CIH SF + (I - SF) x (I - - - ) EHBF
measured systemic clearance (see below) is a consequence of the dual blood supply (Laut, 1977).
1.3 Dose-dependent First-pass Metabolism (Eq. 3)
where SF is the fraction of portal venous flow which is shunted to the systemic venous system, and EHBF is the effective hepatic blood flow, consisting of the hepatic arterial flow and the non-shunted portal venous flow. In this equation, the term CIH/EHBF again represents the hepatic extraction ratio. Comparing equation 3 with equation I, several differences can be seen. In equation 3 an important determinant of bioavailability is the shunt fraction (SF); as SF approaches unity, the bioavailability approaches I and the EHBF approaches the value for hepatic arterial flow. Since hepatic arterial flow (representing approximately one third of splanchnic blood flow in normal subjects) is usually maintained and may even be increased in cirrhotic patients, hepatic clearance, physiologically determined as the product of EHBF and ER (equation 2), may remain relatively large, if hepatocyte function does not substantially deteriorate. Figure I illustrates the relationships between portosystemic shunting, clearance and bioavailability for drugs with moderate (0.5) and high (0.8) hepatic extraction ratios. The theoretical values for clearance and bioavailability are calculated from equation 3 and are based on the assumptions that hepatic arterial flow is maintained, and that the hepatic extraction ratio is unchanged. The latter assumption mayor may not be valid; indirect measurements in cirrhotics using model compounds suggest that intrinsic clearance is relatively unaffected. However, a recent direct measurement of d-propranolol hepatic extraction in cirrhosis demonstrates a substantial (44 %) fall mextraction and an even more dramatic decrease in calculated intrinsic hepatic clearance (Pessayre et aI., 1978). Nevertheless, it is likely that some of the differences between observed bioavailability and that which would be predicted on the basis of the
For drugs which have linear kinetics, the concentrations in blood or plasma are proportional to the size of the oral dose, and bioavailability is independent of dose. However, a few drugs seem to show dose dependent bioavailabiIity including: salicylamide (Barr et aI., 1973); chlormethiazole (Jostell et aI., 1978) and 5-fluorouracil (Christophidis et aI., 1978). Data are controversial concerning dose-dependent absorption of propranolol. Shand and Rangno (I 972) observed that a threshold dose of approximately 30mg of propranolol was needed before plasma levels could be observed after a single oral dose. Gomeni et al. (I 977), using different analytical methodology, were unable to confirm this nonlinearity, although they found a longer half-life after low dose (I Omg) oral administration. Subsequent investigations suggest that a threshold may indeed be present, but at lower doses than originally observed (see Routledge and Shand, 1979). Mechanisms responsible for dose dependent availability are unknown. There is a lack of solid experimental data regarding the hepatoportal concentrations of drugs after oral or intravenous administration. Depending on the rate of absorption, volume of distribution and rate of distribution from plasma to tissues, it is possible to achieve significantly higher hepatoportal concentrations after oral administration than are seen after intravenous doses (Rowland, 1973). Under such circumstances, 'saturation' of first-pass metabolism is possible. Differences in patterns of metabolites have been reported after the oral versus intravenous administration of propranolol (Paterson et aI., 1970) and hydrallazine (Talseth, 1977), which are consistent with saturation of hepatic enzyme systems, or intestinal mucosal first-pass effects. It is perhaps surprising how few drugs demonstrate dose dependent bioavailability; it is uncertain, however, whether saturable first-pass metabol-
427
Hepatic First-pass Metabolism in Uver Disease
ism is more likely under conditions of hepatic dysfunction. Such a mechanism is consistent with observations regarding bioavailability and systemic clearance which will be presented in the next section.
2. The Influence of Hepatic Dysfunction on First-pass Metabolism of Specific Drugs Quantitative assessment of first-pass metabolism requires the comparison of data obtained after intravenous administration of a drug with that resulting from oral administration. A drug given intravenously has 100 % bioavailability, and, assuming linear kinetics, the area under the resulting blood (or plasma) concentration-time curve extrapolated to infinity (AUC iy]'0) serves as a reference value against which to compare the area following oral administration (AUCo1 0>. Bioavailability is then simply defined as:
there are very few studies which have measured bioavailability and estimated first-pass metabolism in patients with liver disease. The drugs for which such information is available are: chlormethiazole, labetalol, lignocaine (lidocaine), paracetamol (acetaminophen), pentazocine, pethidine (meperidine), and propranolol.
2.1 Chlormethiazole (Pentikainen et aI., 1978)
Chlormethiazole, a sedative/hypnotic agent, was studied in 8 men with biopsy proven cirrhosis and 6 age matched healthy male volunteers. Each subject received orally 192mg of chlormethiazole base and, on another occasion, an equimolar dose given intravenously. Blood samples were collected for at least 5 elimination half-lives and chlormethiazole concentrations measured by mass fragmentography. The bioavailability of chlormethiazole in the control subjects compared with the cirrhotic subjects was AUCo] ~/Dosea F (Eq.4) 11.8 ± 2.9% versus 136 ± II %, respectively. The AUCjy] ~/Dos~y latter figure, indicating an oral bioavailability of greater than 100 % , is probably methodological, since Of course, if the value for F is less than one, it is not the concentrations after oral and intravenous adnecessarily the result of first-pass hepatic metabolism. ministration to the cirrhotic subjects were similar. Low bioavailability following oral administration Other sources of nonlinearity, such as hepatic uptake could result from poor absorption, from metabolism or distribution, might also explain these results. by micro-organisms in the alimentary tract (RowOf interest is the observation that, although there land, 1973) or from metabolism in the gut wall, as was an II-fold increase in bioavailability, the sysdemonstrated for chlorpromazine and L-dopa temic clearance after intravenous administration is (Gibaldi and Perrier, 1974). However, strong indica- only modestly reduced, from 18.1 ± 1.2ml/min/kg tions that first-pass metabolism is responsible for an in normals to 12.8 ± 1.7ml/min/kg in the cirrhotic observed low bioavailability following oral ad- patients, a fall of 30 %. As discussed earlier, this 'disministration is a high nonrenal systemic clearance crepancy' between systemic clearance and bioavailafter intravenous administration. Unfortunately, in- ability may be related to the dual blood supply, or to travenous data are not always available, for a variety saturation of hepatic enzymes in the cirrhotic patient of reasons. When only data after oral administration after oral, but I,lot intravenous administration. can be obtained, a short half-life and extensive meta- Because of the similarity in concentrations after either bolism is suggestive evidence for substantial first-pass the oral or intravenous route, the latter possibility metabolism. seems less likely and, even if it occurred, could not acAlthough there are an increasing number of count for the bioavailability value of greater than reports in the literature describing the influence of 100 %. Another finding, of some clinical relevance hepatic dysfunction on systemic clearance of drugs, (as will be discussed later) is the finding that the area
428
Hepatic First-pass Metabolism in Liver Disease
under the plasma concentration-time curve after oral administration (AUCeJ Q) is increased by a factor of 17 in the cirrhotic patient, compared with the II-fold increase in bioavailability.
2.2 Labetalol (Homeida et ai., 1978) The disposition of this relatively new hypotensive agent, a combined a- and ~-adrenoceptor blocking drug, was compared in 10 patients with histologically proven cirrhosis and 7 normal control subjects. The controls were aged 22 to 42 years while the mean age of the patients was 57.7 years. After both oral and intravenous administration of the drug, plasma samples were collected for 2 half-lives and labetalol was analysed by spectrofluorometry. The sensitivity and accuracy of the method are not stated. In normal subjects, labetalol had a bioavailability of 33 ± 3 %. In the cirrhotic patients bioavailability was 63 ± 7 %. The authors do not discuss systemic clearance, but it can be calculated from their values for AUCiv] '0 and dose. In normal subjects, the clearance is calculated as 2.8L/min, while in the cirrhotics it is 2.0L/min. In view of the figure for bioavailability in normal subjects, and the fact that the clearance in normals exceeds estimated hepatic plasma flow, there is some inconsistency in these data. Renal clearance is apparently not an explanation, since less than 5 % of labetalol is excreted in the urine as unchanged drug. Although there may be some question about the absolute values for clearance, the maintenance of a relatively high systemic clearance in the face of a 2fold increase in bioavailability is again present in this study.
2.3 Lignocaine (Tschang et ai., 1977) Lignocaine (IOOmg IV and 200mg PO) and antipyrine (I Omg / kg) were administered intravenously and orally to 3 healthy controls, 6 cirrhotics with evidence of portal hypertension, and 3 patients with alcoholic hepatitis. The bioavaiiabiJity of lignocaine in
the normal volunteers was 0.33, compared with 0.65 in the cirrhotics and 0.49 in the patients with alcoholic hepatitis. The clearance was decreased from 10.07 ± Iml/min/kg in normals to 5.82 ± 1.3 in the cirrhotic subjects. Values for antipyrine bioavailability are not presented. Lignocaine is usually not given oral1y for therapeutic purposes, but, like antipyrine, has been used as a model compound to study the influence of hepatic blood flow and enzyme activity on drug clearance and first-pass effect.
2.4 Paracetamol (Arnman and Olsson, 1978) Studies were performed in I 5 patients without liver disease, 2 I patients with cirrhosis and 4 patients with secondary liver cancer. Only oral paracetamol was investigated, data being presented on samples drawn for 6 hours. The AUCeJ '0 was 50% above control values both in the cirrhotics and in the patients with metastatic liver cancer, and there was a tendency for patients with portocaval shunts to have even larger values. However, since the relative contribution of decreased clearance versus increased bioavailability cannot be estimated without intravenous dosing, this study permits no conclusions to be drawn concerning paracetamol first-pass effect.
2.5 Pentazocine (Neal et aI., 1979) This study involved 8 patients with biopsy proven cirrhosis and 4 age matched subjects. Pentazocine was given to all study participants in oral and intravenous forms and blood samples obtained for 24 hours following drug administration. Pentazocine was analysed by gas-liquid chromatography with electron capture detection. In the cirrhotic patients, the bioavailabiJity of pentazocine was substantially increased: 0.68 ± 0.21 compared with 0.18 ± 0.05 in the control group. The blood clearance of pentazocine was substantially reduced in the patients: 675 ± 296ml/min com-
429
Hepatic First-pass Metabolism in Uver Disease
pared with 1246 ± 236ml/min for the normal subjects. It is noteworthy that the combined effect of increased bioavailability and decreased blood clearance on the AUCol 0 was multiplicative, not additive and that systemic clearance decreased by less than 50 % in the presence of a greater than 3-fold increase in bio'availability.
2.6 Pethidine (Neal et ai., 1979) The study involved the same subjects as described above for pentazocine and blood sampling was again performed over a 24-hour period. Pethidine was analysed by gas-liquid chromatography with flame ionisation detection. In the cirrhotic patients bioavailability was increased from the normal value of 0.48 ± 0.13 to 0.87 ± 0.27, and blood clearance was reduced from 900 ± 316 to 573 ± 158m1/min. Again the total effect of these changes on AUCol ~ was multiplicative, and the systemic blood clearance in cirrhosis predicts a lower bioavailability than actually observed in the study.
3. Predicting Increased Bioavailability in Patients with Hepatic Dysfunction For the practising physician it is important to predict which drugs in which patients are likely to show substantial changes in bioavailability as the result of liver disease. Few data are available on this subject, but it is apparent that both the pharmacokinetic characteristics of the drug and the type of liver disease will be important determinants of whether increases in bioavaiiabiIity will be seen.
3. I Properties of the Drug In the study of pentazocine and pethidine bioavailability in cirrhotic patients (Neal et ai., 1979),
1
1.0
;;::
~()~, ' ~;; ¥ '/
u '2 J:: u
2.7 Propranolol (Branch et ai., 1977)
",,'''
~ ..... ()'O"
!I c:
,-?
"
jects.
0.8 Cl
.5 c:
0.6 ~.g Q)..!!! ~
:>
~ "'.OU Q)
0.4
c:
The disposition of propranolol has been studied in 15 normal subjects and 6 patients with cirrhosis. They administered unlabelled drug orally and tritiated propranolol intravenously which is a useful technique for measuring bioavailability that reduces intrapatient variation due to time-dependent changes in clearance. In the normals, propranolol bioavailability was 0.36 ± 0.024 and in the cirrhotics it was 0.60 ± 0.08. Systemic clearance was 898ml/min in normals, compared with 558ml/min in the cirrhotic subjects. In this study there is good agreement between the extent of increase in bioavailability and the decrease in clearance. In a follow up to this preliminary report, Wood et ai. (1978) showed a correlation between antipyrine and indocyanine green clearances and the clearance of propranolol in the cirrhotic sub-
1.0
1Ju
.2
.... ·E
"'lac: ....'"
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(J..!!!
0
0
20
40
60
80
0 100
~
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LI.._
Percentage shunting of portal venous flow
Fig. 7. Relationship between portosystemic shunting. clearance. and bioavailability. The horizontal axis indicates the percentage of portal blood flow which bypasses the liver. Normals would have no shunting. severe cirrhotics might have 100% shunting. The left hand vertical scale and· solid line shows the systemic clearance (as a fraction of total splanchnic flow) for moderate (ER = 0.5) and high (ER = 0.8) extraction ratio drugs as the percent shunting of portal flow increases. The right hand vertical scale and dashed line shows the corresponding bioavailability values for various degrees of shunting. See text for assumptions and discussion.
Hepatic First-pass Metabolism in Liver Disease
it was found that there was a considerably larger change in pentazocine bioavailability (278 %) than in pethidine bioavailability (81 %). In normal subjects, pentazocine had a much lower bioavailability (0.18) than did pethidine (0.48). If, as seems likely, the findings with these 2 drugs are generally applicable then those drugs with the largest hepatic extraction ratios under normal conditions have the greatest potential for relative increases in bioavailability in patients with hepatic disease. This is consistent with equations I and 3, which show that the shunt fraction (SF) replaces the hepatic extraction ratio as the most important determinant of bioavailability. Figure I also illustrates this same point, with the slope of the increase in bioavailability being steeper for the high extraction ratio drug as compared with the drug with a smaller extraction ratio.
3.2 Characteristics of the Patient No studies have been reported which attempt to correlate patient characteristics with changes in bioavailability. However, in studying the systemic clearance of propranolol (Branch and Shand, 1976), the greatest changes were found in cirrhotic patients with low serum albumin concentrations, raised serum bilirubin and prolonged prothrombin times. Little correlation was found with other tests of liver function. These authors make the point, however, that correlations are likely to be dependent on the type of liver disease and that liver enzymes such as SGPT might serve a useful predicting role in, for example, acute viral hepatitis. It should be emphasised that correlations found to be relevant with regard to systemic clearance will not necessarily be applicable to presystemic metabolism. Several of the studies discussed above have shown that increases in bioavailability may be larger than would be predicted by the observed changes in systemic clearance; a possible explanation for this has been discussed earlier. Clinically, the quantitative estimation of portosystemic shunting is difficult, and none of the readily available laboratory or radiological tests provide
430
Table I. Drugs known or suspected to have high hepatic first-pass metabolism
Acety!salicylic acid Alprenolol Chlormethiazole Chlorpromazine Isoprenaline Labetalol Lignocaine (lidocaine) Methylphenidate Metoprolol Morphine
Nitroglycerine Nortriptyline Paracetamol Pentazocine Pethidine (meperidine) Prazosin Propoxyphene Propranolol Salicylamide
useful quantitative information. It is clear from those studies which have included patients with surgically created portocaval shunts, that such patients have generally higher bioavailability and lower clearance, although the mechanism is unclear and may be related to decreased hepatocyte function in addition to increased shunting.
4. Clinical Implications The clinical relevance of changes in bioavailability due to hepatic disease is clear, even though the number of experimental studies is small. If drugs normally undergo substantial hepatic first-pass metabolism (e.g. those drugs listed in table I), large increases in bioavailability and decreases in systemic blood clearance are to be expected. When such drugs are administered orally, the increase in bioavailability and decrease in clearance will have a multiplicative effect on the total area under the blood concentrati0n-time profile. This means that a SO % decrease in clearance, and a 4-fold increase in bioavailability results in an 8fold increase in the AUCol '0 in cirrhotic subjects, as we have shown with pentazocine (Neal et aI., 1979). If there is a linear proportionality between concentration and response, then the effect on response will also be multiplicative. Thus, any differences in the intensity andlor duration of response observed between controls and patients with liver disease when an
Hepatic First-pass Metabolism in Uver Disease
equivalent dose of a high clearance compound (table I) is given intravenously, will be further accentuated by oral administration. Finally, in patients without liver disease there is ordinarily little accumulation of those high clearance drugs which have short half-lives. In cirrhotic patients who have decreased systemic clearances and longer half-lives, clinically significant accumulation of these drugs may occur in multiple dose regimens, resulting in toxicity which appears after several doses, but not with the first dose. Physicians who use drugs with high first-pass metabolism in cirrhotic patients, or in patients with other conditions where hepatic flow or function may be impaired (Benowitz and Meister, 1976; Jaillon et aI., 1979) should be aware of the necessity to reduce the dose and increase the dosing interval to avoid excessive concentrations of drug.
Acknowledgements Supported in part by National Institutes of Health Grant GM22209. Terrence F. Blaschke is a Burroughs Wellcome Scholar in Clinical Pharmacology, and the recipient of a Research Career Development Award (GM00407) from the NIH. Peter C. Rubin is the recipient of a Research Fellowship from the American Heart Association. We wish to thank Kathleen Giacomini for critical review and Linda Halloran for preparation of the manuscript.
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Author's address: Prof. Terrence F. Blaschke. Division of Clinieal Pharmacology. Room S155. Stanford University Medical Center. Stanford. CA 94305 (USA).
