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Liver Disease and Drug Therapy
Symposium on Individualization of Drug Therapy
Liver Disease and Drug Therapy Martin Black, M.D.* MD.*
Recognition of the liver's key role role in drug biotransformation has prompted investigations into the effects of liver disease on drug action and disposition. This academically predictable area of intensive study was given additional impetus by the clinical observation that patients with liver disease experienced an altered sensitivity to some therapeutic agents. 44 • 17 Despite the fact that much has been learned in less than 20 years of investigation, it cannot yet be claimed that the present state of the art permits the physician to individualize therapy in the same manner as is feasible for patients with renal disease (see pp. 977 to 985). In no small way this is more a reflection of the greater complexity of the liver's physiologic role in drug disposition compared with that of the kidney than of inadequate study. Accordingly, this presentation will concentrate on reviewing data which confirm that problems with drug therapy in patients with liver disease have a pharmacologic basis. Exploitation of such information in order to fashion individualized treatment regimens remains, unfortunately, a goal for the future, rather than an immediate capability. Investigations of liver disease and drug therapy have utilized either experimental models of liver disease or patients with any of a variety of hepatic disorders. In general, these investigations have been more successful in documenting abnormalities in the experimental models than in the living patient. The reasons for this basic discrepancy are not hard to find. Experimental models of liver disease have, for the most part, consisted of acute or chronic poisoning with chemicals such as carbon tetrachloride, which produce a well-circumscribed area of hepatocellular necrosis of finite duration. Human liver disease, on the other hand, comprises an assortment of inflammatory, degenerative, and neoplastic insults to hepatic parenchyma and supporting structures. The resulting damaged organ varies widely from one patient to another in terms of parenchymal, synthetic, and metabolic function, biliary excretory ability, and hepatic blood flow, each of which have been shown to have separate and potentially additive or competitive effects on drug disposition. The histologic section in Figure 1, for example, reveals the typical ':'Associate Professor of Medicine and Pharmacology and Head, Liver Unit, Temple University Health Sciences Center, Philadelphia, Pennsylvania
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Figure 1. Liver biopsy from patient with alcoholic liver disease, showing fatty infiltration, centrilobular necrosis, alcoholic hyaline (arrow), inflammatory cells and scarring (hematoxylin and eosin; magnification xX 470).
characteristics of alcohol-related liver disease. Its combination of fatty infiltration, acute inflammation, cytoplasmic change, necrosis, fibrosis, and disturbance of blood flow is a unique form of liver disease which has not been reproduced in laboratory animals. Nor have animal models been developed for acute viral hepatitis, for the various forms of chronic aggressive hepatitis, or for typical intrahepatic cholestasis. Other factors which influence drug handling are not infrequently present in the patient with liver disease. These include chronic alcohol ingestion, concomitant sedative or other drug administration, altered body water compartments, hypoalbuminemia, and other organ disease. As an area of "steady state" investigation, the patient with liver disease hardly presents an ideal choice. Since no good experimental model of human liver disease exists, relevant information can only be provided by presenting clinical and biochemical data from well-studied patients with a full description of the patient's disease. Widely differing conclusions about the drug-metabolizing
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abilities of patients with liver disease (which have frequently occurred in the past) may then be rationally explained.
ACTIVITIES OF HEPATIC DRUG-METABOLIZING ENZYMES IN LIVER DISEASE Methods of investigating the effects of liver disease on drug action and disposition have included in vitro assay of hepatic drug-metabolizing enzymes, pharmacokinetic analysis of drug disposition in vivo, and carefully controlled investigation of measurable drug effects. Little information is presently available on the activities of drug metabolizing enzymes in human liver disease, largely because of the requirement for greater amounts of tissue for their assay than can readily be obtained. '6 in Germany have claimed to be able to Schoene and co-workers 16 measure cytochrome P450 content, NADPH cytochrome c reductase, and aminopyrine-N -demethylase and nitroanisole-Othe activities of aminopyrine-N-demethylase demethylase (2 cytochrome P450-requiring enzymes) in less than 30 mg of tissue, an amount capable of being provided by percutaneous needle biopsy. Patients with normal liver were studied as well as those whose liver abnormality was classified as "mild hepatitis," "moderate hepatitis," or "severe hepatitis and cirrhosis." NADPH cytochrome-c-reductase was normal in all subjects, but cytochrome P450 was reduced over 40 per cent in the "severe hepatitis and cirrhosis" category, as was aminopyrine-N-demethylase aminopyrine-N -demethylase and nitroanisole-O-demethylase. Gold and Ziegler77 also reported on aminopyrine-N-demethylase activity in liver biopsy samples from patients with a wide variety of liver diseases. They were not able to demonstrate significant decrease in enzyme activity in any of their categories of liver disease (which were not accompanied by any clinical or biochemical information necessary to assess the severity of the liver disease), although dimethylaniline-Noxidase (a noncytochrome P450-requiring enzyme) was reduced in the cirrhotic group.
DRUG HALF-LIFE STUDIES IN LIVER DISEASE An example of disagreement about the effects of human liver disease on drug biotransformation is afforded by some studies that have been carried out on the metabolic clearance rate - expressed as plasma halflife-of the oral hypoglycemic agent tolbutamide. Tolbutamide is a substrate of the cytochrome P450 oxidation system of liver microsomes, and this is its major pathway of elimination; it has been widely used as a "model" drug to investigate the influence of many types of disease on drug biotransformation. 66 20 in Japan reported that five of ten paIn 1963, Ueda and co-workers 20 tients with "cirrhosis" (not established histologically) had prolonged tolbutamide half-lives as compared to normal subjects. Unfortunately, the
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clinical information provided did not permit adequate characterization of the hepatic disease. Shortly after this paper appeared, Nelson 13 in New York presented his data on this subject which suggested considerable overlap between results in ten patients with chronic liver disease and his own and previously reported results in normal subjects. In this report, the type of hepatic disease was more precisely characterized. The full circle of results regarding "tolbutamide metabolism and liver disease" was completed by a more recent report by Held and von 01dershausen 88 from Tubingen in West Germany. They reported shortening of the plasma tolbutamide half-life in patients with acute hepatitis, the results apparently becoming more prolonged - and hence back to norprolonged-and mal-after malafter jaundice disappeared. Technical and statistical shortcomings in two or more of these papers contributed to the conflict provided by the widely differing inferences of each study. It should be noted that tolbutamide-induced hypoglycemia has rarely been reported in patients with liver disease. Similar disagreements have been reported with respect to the metabolism of phenylbutazone and pentobarbitone in pati~nts patients with liver disease. Two reports suggested that phenylbutazone was metabolized more rapidly by patients with chronic liver disease than in normal subjects. 22 , 21 1o (studying patients with acute and chronic liver Levi and co-workers 10 disease) observed, however, that if attention was paid to coincidental ingestion of enzyme-inducing drugs, then liver disease "per se" appeared to adversely affect phenylbutazone metabolism. In a study that employed an excellent experimental design, Mawer ll and co-workers investigated the plasma clearance of amylobarbitone co-workersll (Amytal)-a drug which is metabolized by the cytochrome P450-dependent microsomal oxidation system- in ten patients, eight of whom had histologically proved cirrhosis.;:( cirrhosis." After defining the normal range for amylobarbitone clearance in normal subjects, they demonstrated that clearance of the drug was impaired in five of the cirrhotics. The only clinical or biochemical feature which differentiated these five from the others who did not show impaired drug clearance was the presence of a low serum albumin, suggesting that there may exist a parallelism in human liver disease between albumin synthesis and cytochrome P450oxidation, dependent drug oxidation.
INFLUENCE OF LIVER DISEASE ON DRUG TREATMENT REGIMENS With the possible exception of the studies on barbiturates, investigations of effects of liver disease on drug metabolism have been academic exercises seeking to identify general phenomena rather than attempts to therapy, determine how the presence of liver disease influenced specific therapy. ':'Ofinterest ':'Of interest in discussing the patients was the author's comment that "when selecting patients for the study we were unable to find a sufficient number who were not receiving other drugs," drugs."
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This approach has been changed in the last two or three years, and new information has become available which indicates that certain forms of therapy may be affected significantly by the presence of liver disease. Niridazole (Ambilhar) is presently being used widely in the treatFaigle"5 showed that in a region of Brazil where ment of schistosomiasis. Faigle schistosomiasis is endemic, niridazole produced side effects on the central nervous system more frequently in patients with the hepatosplenic form of the disease than in those with the intestinal form. He attributed this to the presence of elevated blood levels of unmetabolized drug in these patients, and postulated that this resulted from shunting of portal blood away from the liver (integrity of liver parenchymal function is normally well preserved in these patients). The effects of alteration in vascular perfusion of the liver on drug disposition are also well demonstrated by studies on lidocaine clearance. 19 reported that plasma clearance of lidocaine Thomson and co-workers 19 was prolonged significantly in eight patients with "advanced" alcoholic liver disease. Since the elimination of this drug has been observed to be fiOW,lB it is probable that altered vascular perdependent on hepatic blood flOW,18 fusion of the liver rather than parenchymal disease was the major factor in producing the impaired drug clearance. Another therapeutic agent which is used commonly in patients with liver disease is prednisone. This agent has proved to be of significant value in the treatment of certain categories of liver disease. Powell and Axelson Axelson'"15 drew attention to the prevailing belief that prednisone must be converted to the biologically active prednisolone by the hepatic enzyme 1l{3-hydroxydehydrogenase before producing its therapeutic effect. effect."9 11{3-hydroxydehydrogenase They studied serum prednisolone levels after oral prednisone administration to patients with acute or chronic liver disease, and noted that in several patients plasma prednisolone levels were significantly lower than those observed after prednisone administration to normal subjects. In one patient, studied serially during and after an attack of hepatitis, clinical recovery was accompanied by a significant improvement in the generation of prednisolone from a standard dose of prednisone. The importance of this observation is not clear because the same authors demonstrated decreased albumin binding of prednisolone in the plasma of patients with liver disease, this having the effect of making the lower concentration of drug in the plasma as effective as a higher concentration 14 observed also that the plasma half-life of in the normal. They and others 14 prednisolone may be prolonged in patients with liver disease. Perhaps the most significant evidence that liver disease can adversely affect therapeutic regimens comes from three separate studies on azathioprine (Imuran, an immunosuppressive agent). This agent, though less effective, has been used in categories of liver disease similar to those in which prednisone is employed. Though it was originally introduced into clinical medicine as a "slow-release" form of 6-mercaptopurine,3 the biologically active form of either drug has not been identified. Bach and Dardenne 11 in Paris have utilized a bioassay system for measuring plasma immunosuppressive activity after administration of azathioprine. This system depends upon the induced inhibition of rosette
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:15S_ formation by normal lymphocytes. After the oral administration of 35S_ labeled azathioprine to seven normal subjects, rosette-inhibiting activity developed in the plasma, its titer closely following the kinetics of plasma with acute hepatitis and 35 S clearance. The same type of study in a patient "vith one with cirrhosis revealed that the kinetics of 35S clearance were undisturbed, but no rosette-inhibiting activity could be detected at any time in the plasma. Similar observations have been documented by two other groupsl2.22 in the United Kingdom in such diverse clinical situations as groups12.22 post-liver transplantation, active chronic hepatitis, and primary biliary cirrhosis. In one of these studies,12 the ability to develop plasma rosetteinhibiting activity after azathioprine administration was inversely related to episodes of cholestasis in a post-liver transplantation patient.
CONCLUSIONS In conclusion, it can be stated that recent investigations have established that the existence of hepatic disease in a patient may significantly influence the efficacy or potential toxicity of a number of therapeutic regimens. As investigational approaches have moved away from the traditional half-life studies of rarely used therapeutic agents to a more clinically relevant type of study, so has the information gained been more pertinent and capable of being applied at the bedside. Although this ofliver presentation has concentrated on reviewing the effects of liver disease on disposition of drugs, other studies have indicated that the patient with liver disease can be demonstrated to exhibit altered sensitivity to the actions of drugs. The patient with significant liver disease presents a serious therapeutic problem which demands the extra attention that clinical experience has suggested is required.
REFERENCES 1. l. Bach, J. F., and Dardenne, M.: Serum immunosuppressive activity of azathioprine in normal subjects and patients with liver diseases. Proc. Roy. Soc. Med., 65:260-263, 1972. ]., and Weiner, M.: Metabolism of drugs in subjects with Laennec's 2. Brodie, B. B., Burns, J. J., cirrhosis. Med. Exp., 1 :290-292, 1959. 3. Elion, G. B.: Biochemistry and pharmacology of purine analogues. Fed. Proc., 26:898-903, 1967. 4. Fagin, I. D., and Thompson, F. M.: Cirrhosis of the liver: An analysis of 71 cases. Ann. Intern. Med., 21 :285-297, 1944. 5. Faigle, J. W.: Blood levels of a schistosomicide in relation to liver function and side effects. Acta Pharmacol., 29, suppl. 3, 233-239, 1971. 6. Glogner, P., Lange, H., and Pfab, R.: Tolbutamidstoffwechsel bei Niereninsuffizienz. Med. Welt, 52:2876-2878, 1968. 7. Gold, M. S., and Ziegler, D. M.: Dimethylaniline N-oxidase and aminopyrine Ndemethylase activities of human liver tissue. Xenobiotica, 3:179-189,1973. 3: 179-189, 1973. 8. Held, H., and von Oldershausen, H. F.: Drug metabolism in acute and chronic liver disease. Fifth Meeting of the European Association for the Study of the Liver. Berne, Switzerland, 1970. 9. Jenkins, J. S., and Sampson, P. A.: Conversion of cortisone to cortisol and prednisone to prednisolone. Brit. Med. J., 2:205-207, 1967. 10. Levi, A. J., Sherlock, S., and Walker, D.: Phenylbutazone and isoniazid metabolism in pa1275-1279, 1968. tients with liver disease in relation to previous drug therapy. Lancet, 1: 1275-1279,1968.
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11. Mawer, G. E., Miller, N. E., and Turnberg, L. A.: Metabolism of amylobarbitone in patients with chronic liver disease. Brit. J. Pharmacol., 44:549-560, 1972. 12. MitchelI, Mitchell, C. G., Eddleston, A. L. W. F., Smith, M. G. M., and WilIiams, Williams, R.: Serum immunosuppressive activity due to azathioprine and its relation to hepatic function after liver transplantation. Lancet, 1: 1196-1199, 1970. 13. Nelson, E.: Rate of metabolism of tolbutamide in test subjects with liver disease or with 'l'enal function. Amer. J. Med. ScL, Sci., 248:657-659, 1964. impaired renal 14. Peterson, R. E.: Adrenocortical steroid metabolism and adrenal cortical function in liver disease. J. Clin. Invest., 39:320-331, 1960. 15. PowelI, Powell, L. W., and Axelson, E.: Corticosteroids in liver disease: Studies on the biological conversion of prednisone to prednisolone and plasma protein binding. Gut, 13 :690-696, 1972. 16. Schoene, B., Fleischmann, R. A., Remmer, H., and von Oldershausen, H. F.: Determination of drug metabolizing enzymes in needle biopsies of human liver. Eur. J. Clin. Phar4:65-73,1972. macol., 4:65-73, 1972. Bullard, J. C., and Ingelfinger, F. J.: The effect of bar17. Sessions, J. T., Minkel, H. P., BulIard, biturates in patients with liver disease. J. Clin. Invest., 33:1116-1127,1954. 18. Stenson, R. E., Constantino, R. T., and Harrison, D. C.: Interrelationships of hepatic blood flow, cardiac output and blood levels of lidocaine in man. Circulation, 43:205-212,1971. 43:205-212, 1971. 19. Thomson, P. D., Melmon, K. K L., Richardson, J. A., Cohn, K., K, Steinbrunn, W., Cudihee, R., and Rowland, M.: Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann. Intern. Med., 78:499-508, 1973. 20. Ueda, H., Sakurai, T., Ota, M., Nakajima, A., Kamii, K, K., and Maezawa, H.: Disappearance mellitus, liver cirrhosis, and renal rate of tolbutamide in normal subjects and in diabetes melIitus, disease. Diabetes, 12:414-419,1963. 21. Weiner, M., Chenkin, T., and Burns, J. J.: Observations on the metabolic transformation Sci., and effects of phenylbutazone in subjects with hepatic disease. Amer. J. Med. ScL, 228:36-39, 1954. 22. Whelan, G., and Sherlock, S.: Immunosuppressive activity in patients with active chronic hepatitis and primary biliary cirrhosis treated with azathioprine. Gut, 13:907-914, 1972. Departments of Medicine and Pharmacology Temple University Health Sciences Center Philadelphia, Pennsylvania 19140
Liver Disease and Drug Therapy Martin Black, M.D.* MD.*
Recognition of the liver's key role role in drug biotransformation has prompted investigations into the effects of liver disease on drug action and disposition. This academically predictable area of intensive study was given additional impetus by the clinical observation that patients with liver disease experienced an altered sensitivity to some therapeutic agents. 44 • 17 Despite the fact that much has been learned in less than 20 years of investigation, it cannot yet be claimed that the present state of the art permits the physician to individualize therapy in the same manner as is feasible for patients with renal disease (see pp. 977 to 985). In no small way this is more a reflection of the greater complexity of the liver's physiologic role in drug disposition compared with that of the kidney than of inadequate study. Accordingly, this presentation will concentrate on reviewing data which confirm that problems with drug therapy in patients with liver disease have a pharmacologic basis. Exploitation of such information in order to fashion individualized treatment regimens remains, unfortunately, a goal for the future, rather than an immediate capability. Investigations of liver disease and drug therapy have utilized either experimental models of liver disease or patients with any of a variety of hepatic disorders. In general, these investigations have been more successful in documenting abnormalities in the experimental models than in the living patient. The reasons for this basic discrepancy are not hard to find. Experimental models of liver disease have, for the most part, consisted of acute or chronic poisoning with chemicals such as carbon tetrachloride, which produce a well-circumscribed area of hepatocellular necrosis of finite duration. Human liver disease, on the other hand, comprises an assortment of inflammatory, degenerative, and neoplastic insults to hepatic parenchyma and supporting structures. The resulting damaged organ varies widely from one patient to another in terms of parenchymal, synthetic, and metabolic function, biliary excretory ability, and hepatic blood flow, each of which have been shown to have separate and potentially additive or competitive effects on drug disposition. The histologic section in Figure 1, for example, reveals the typical ':'Associate Professor of Medicine and Pharmacology and Head, Liver Unit, Temple University Health Sciences Center, Philadelphia, Pennsylvania
Vo!. 58, No. 5, September 1974 Medical Clinics of North America- Vol.
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MARTIN BLACK
Figure 1. Liver biopsy from patient with alcoholic liver disease, showing fatty infiltration, centrilobular necrosis, alcoholic hyaline (arrow), inflammatory cells and scarring (hematoxylin and eosin; magnification xX 470).
characteristics of alcohol-related liver disease. Its combination of fatty infiltration, acute inflammation, cytoplasmic change, necrosis, fibrosis, and disturbance of blood flow is a unique form of liver disease which has not been reproduced in laboratory animals. Nor have animal models been developed for acute viral hepatitis, for the various forms of chronic aggressive hepatitis, or for typical intrahepatic cholestasis. Other factors which influence drug handling are not infrequently present in the patient with liver disease. These include chronic alcohol ingestion, concomitant sedative or other drug administration, altered body water compartments, hypoalbuminemia, and other organ disease. As an area of "steady state" investigation, the patient with liver disease hardly presents an ideal choice. Since no good experimental model of human liver disease exists, relevant information can only be provided by presenting clinical and biochemical data from well-studied patients with a full description of the patient's disease. Widely differing conclusions about the drug-metabolizing
LIVER DISEASE AND DRUG THERAPY
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abilities of patients with liver disease (which have frequently occurred in the past) may then be rationally explained.
ACTIVITIES OF HEPATIC DRUG-METABOLIZING ENZYMES IN LIVER DISEASE Methods of investigating the effects of liver disease on drug action and disposition have included in vitro assay of hepatic drug-metabolizing enzymes, pharmacokinetic analysis of drug disposition in vivo, and carefully controlled investigation of measurable drug effects. Little information is presently available on the activities of drug metabolizing enzymes in human liver disease, largely because of the requirement for greater amounts of tissue for their assay than can readily be obtained. '6 in Germany have claimed to be able to Schoene and co-workers 16 measure cytochrome P450 content, NADPH cytochrome c reductase, and aminopyrine-N -demethylase and nitroanisole-Othe activities of aminopyrine-N-demethylase demethylase (2 cytochrome P450-requiring enzymes) in less than 30 mg of tissue, an amount capable of being provided by percutaneous needle biopsy. Patients with normal liver were studied as well as those whose liver abnormality was classified as "mild hepatitis," "moderate hepatitis," or "severe hepatitis and cirrhosis." NADPH cytochrome-c-reductase was normal in all subjects, but cytochrome P450 was reduced over 40 per cent in the "severe hepatitis and cirrhosis" category, as was aminopyrine-N-demethylase aminopyrine-N -demethylase and nitroanisole-O-demethylase. Gold and Ziegler77 also reported on aminopyrine-N-demethylase activity in liver biopsy samples from patients with a wide variety of liver diseases. They were not able to demonstrate significant decrease in enzyme activity in any of their categories of liver disease (which were not accompanied by any clinical or biochemical information necessary to assess the severity of the liver disease), although dimethylaniline-Noxidase (a noncytochrome P450-requiring enzyme) was reduced in the cirrhotic group.
DRUG HALF-LIFE STUDIES IN LIVER DISEASE An example of disagreement about the effects of human liver disease on drug biotransformation is afforded by some studies that have been carried out on the metabolic clearance rate - expressed as plasma halflife-of the oral hypoglycemic agent tolbutamide. Tolbutamide is a substrate of the cytochrome P450 oxidation system of liver microsomes, and this is its major pathway of elimination; it has been widely used as a "model" drug to investigate the influence of many types of disease on drug biotransformation. 66 20 in Japan reported that five of ten paIn 1963, Ueda and co-workers 20 tients with "cirrhosis" (not established histologically) had prolonged tolbutamide half-lives as compared to normal subjects. Unfortunately, the
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clinical information provided did not permit adequate characterization of the hepatic disease. Shortly after this paper appeared, Nelson 13 in New York presented his data on this subject which suggested considerable overlap between results in ten patients with chronic liver disease and his own and previously reported results in normal subjects. In this report, the type of hepatic disease was more precisely characterized. The full circle of results regarding "tolbutamide metabolism and liver disease" was completed by a more recent report by Held and von 01dershausen 88 from Tubingen in West Germany. They reported shortening of the plasma tolbutamide half-life in patients with acute hepatitis, the results apparently becoming more prolonged - and hence back to norprolonged-and mal-after malafter jaundice disappeared. Technical and statistical shortcomings in two or more of these papers contributed to the conflict provided by the widely differing inferences of each study. It should be noted that tolbutamide-induced hypoglycemia has rarely been reported in patients with liver disease. Similar disagreements have been reported with respect to the metabolism of phenylbutazone and pentobarbitone in pati~nts patients with liver disease. Two reports suggested that phenylbutazone was metabolized more rapidly by patients with chronic liver disease than in normal subjects. 22 , 21 1o (studying patients with acute and chronic liver Levi and co-workers 10 disease) observed, however, that if attention was paid to coincidental ingestion of enzyme-inducing drugs, then liver disease "per se" appeared to adversely affect phenylbutazone metabolism. In a study that employed an excellent experimental design, Mawer ll and co-workers investigated the plasma clearance of amylobarbitone co-workersll (Amytal)-a drug which is metabolized by the cytochrome P450-dependent microsomal oxidation system- in ten patients, eight of whom had histologically proved cirrhosis.;:( cirrhosis." After defining the normal range for amylobarbitone clearance in normal subjects, they demonstrated that clearance of the drug was impaired in five of the cirrhotics. The only clinical or biochemical feature which differentiated these five from the others who did not show impaired drug clearance was the presence of a low serum albumin, suggesting that there may exist a parallelism in human liver disease between albumin synthesis and cytochrome P450oxidation, dependent drug oxidation.
INFLUENCE OF LIVER DISEASE ON DRUG TREATMENT REGIMENS With the possible exception of the studies on barbiturates, investigations of effects of liver disease on drug metabolism have been academic exercises seeking to identify general phenomena rather than attempts to therapy, determine how the presence of liver disease influenced specific therapy. ':'Ofinterest ':'Of interest in discussing the patients was the author's comment that "when selecting patients for the study we were unable to find a sufficient number who were not receiving other drugs," drugs."
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This approach has been changed in the last two or three years, and new information has become available which indicates that certain forms of therapy may be affected significantly by the presence of liver disease. Niridazole (Ambilhar) is presently being used widely in the treatFaigle"5 showed that in a region of Brazil where ment of schistosomiasis. Faigle schistosomiasis is endemic, niridazole produced side effects on the central nervous system more frequently in patients with the hepatosplenic form of the disease than in those with the intestinal form. He attributed this to the presence of elevated blood levels of unmetabolized drug in these patients, and postulated that this resulted from shunting of portal blood away from the liver (integrity of liver parenchymal function is normally well preserved in these patients). The effects of alteration in vascular perfusion of the liver on drug disposition are also well demonstrated by studies on lidocaine clearance. 19 reported that plasma clearance of lidocaine Thomson and co-workers 19 was prolonged significantly in eight patients with "advanced" alcoholic liver disease. Since the elimination of this drug has been observed to be fiOW,lB it is probable that altered vascular perdependent on hepatic blood flOW,18 fusion of the liver rather than parenchymal disease was the major factor in producing the impaired drug clearance. Another therapeutic agent which is used commonly in patients with liver disease is prednisone. This agent has proved to be of significant value in the treatment of certain categories of liver disease. Powell and Axelson Axelson'"15 drew attention to the prevailing belief that prednisone must be converted to the biologically active prednisolone by the hepatic enzyme 1l{3-hydroxydehydrogenase before producing its therapeutic effect. effect."9 11{3-hydroxydehydrogenase They studied serum prednisolone levels after oral prednisone administration to patients with acute or chronic liver disease, and noted that in several patients plasma prednisolone levels were significantly lower than those observed after prednisone administration to normal subjects. In one patient, studied serially during and after an attack of hepatitis, clinical recovery was accompanied by a significant improvement in the generation of prednisolone from a standard dose of prednisone. The importance of this observation is not clear because the same authors demonstrated decreased albumin binding of prednisolone in the plasma of patients with liver disease, this having the effect of making the lower concentration of drug in the plasma as effective as a higher concentration 14 observed also that the plasma half-life of in the normal. They and others 14 prednisolone may be prolonged in patients with liver disease. Perhaps the most significant evidence that liver disease can adversely affect therapeutic regimens comes from three separate studies on azathioprine (Imuran, an immunosuppressive agent). This agent, though less effective, has been used in categories of liver disease similar to those in which prednisone is employed. Though it was originally introduced into clinical medicine as a "slow-release" form of 6-mercaptopurine,3 the biologically active form of either drug has not been identified. Bach and Dardenne 11 in Paris have utilized a bioassay system for measuring plasma immunosuppressive activity after administration of azathioprine. This system depends upon the induced inhibition of rosette
1056
MARTIN BLACK
:15S_ formation by normal lymphocytes. After the oral administration of 35S_ labeled azathioprine to seven normal subjects, rosette-inhibiting activity developed in the plasma, its titer closely following the kinetics of plasma with acute hepatitis and 35 S clearance. The same type of study in a patient "vith one with cirrhosis revealed that the kinetics of 35S clearance were undisturbed, but no rosette-inhibiting activity could be detected at any time in the plasma. Similar observations have been documented by two other groupsl2.22 in the United Kingdom in such diverse clinical situations as groups12.22 post-liver transplantation, active chronic hepatitis, and primary biliary cirrhosis. In one of these studies,12 the ability to develop plasma rosetteinhibiting activity after azathioprine administration was inversely related to episodes of cholestasis in a post-liver transplantation patient.
CONCLUSIONS In conclusion, it can be stated that recent investigations have established that the existence of hepatic disease in a patient may significantly influence the efficacy or potential toxicity of a number of therapeutic regimens. As investigational approaches have moved away from the traditional half-life studies of rarely used therapeutic agents to a more clinically relevant type of study, so has the information gained been more pertinent and capable of being applied at the bedside. Although this ofliver presentation has concentrated on reviewing the effects of liver disease on disposition of drugs, other studies have indicated that the patient with liver disease can be demonstrated to exhibit altered sensitivity to the actions of drugs. The patient with significant liver disease presents a serious therapeutic problem which demands the extra attention that clinical experience has suggested is required.
REFERENCES 1. l. Bach, J. F., and Dardenne, M.: Serum immunosuppressive activity of azathioprine in normal subjects and patients with liver diseases. Proc. Roy. Soc. Med., 65:260-263, 1972. ]., and Weiner, M.: Metabolism of drugs in subjects with Laennec's 2. Brodie, B. B., Burns, J. J., cirrhosis. Med. Exp., 1 :290-292, 1959. 3. Elion, G. B.: Biochemistry and pharmacology of purine analogues. Fed. Proc., 26:898-903, 1967. 4. Fagin, I. D., and Thompson, F. M.: Cirrhosis of the liver: An analysis of 71 cases. Ann. Intern. Med., 21 :285-297, 1944. 5. Faigle, J. W.: Blood levels of a schistosomicide in relation to liver function and side effects. Acta Pharmacol., 29, suppl. 3, 233-239, 1971. 6. Glogner, P., Lange, H., and Pfab, R.: Tolbutamidstoffwechsel bei Niereninsuffizienz. Med. Welt, 52:2876-2878, 1968. 7. Gold, M. S., and Ziegler, D. M.: Dimethylaniline N-oxidase and aminopyrine Ndemethylase activities of human liver tissue. Xenobiotica, 3:179-189,1973. 3: 179-189, 1973. 8. Held, H., and von Oldershausen, H. F.: Drug metabolism in acute and chronic liver disease. Fifth Meeting of the European Association for the Study of the Liver. Berne, Switzerland, 1970. 9. Jenkins, J. S., and Sampson, P. A.: Conversion of cortisone to cortisol and prednisone to prednisolone. Brit. Med. J., 2:205-207, 1967. 10. Levi, A. J., Sherlock, S., and Walker, D.: Phenylbutazone and isoniazid metabolism in pa1275-1279, 1968. tients with liver disease in relation to previous drug therapy. Lancet, 1: 1275-1279,1968.
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