Effects of liver disease on pharmacokinetics. An update

Liver disease can modify the kinetics of drugs biotransformed by the liver. This review updates recent developments in this field, with particular emphasis on cytochrome P450 (CYP). CYP is a rapidly expanding area in clinical pharmacology. The information currently available on specific isoforms involved in drug metabolism has increased tremendously over the latest years, but knowledge remains incomplete. Studies on the effects of liver disease on specific isoenzymes of CYP have shown that some isoforms are more susceptible than others to liver disease. A detailed knowledge of the particular isoenzyme involved in the metabolism of a drug and the impact of liver disease on that enzyme can provide a rational basis for dosage adjustment in patients with hepatic impairment. The capacity of the liver to metabolise drugs depends on hepatic blood flow and liver enzyme activity, both of which can be affected by liver disease. In addition, liver failure can influence the binding of a drug to plasma proteins. These changes can occur alone or in combination; when they coexist their effect on drug kinetics is synergistic, not simply additive. The kinetics of drugs with a low hepatic extraction are sensitive to hepatic failure rather than to liver blood flow changes, but drugs having a significant first-pass effect are sensitive to alterations in hepatic blood flow. The drugs examined in this review are: cardiovascular agents (angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, calcium antagonists, ketanserin, antiarrhythmics and hypolipidaemics), diuretics (torasemide), psychoactive and anticonvulsant agents (benzodiazepines, flumazenil, antidepressants and tiagabine), antiemetics (metoclopramide and serotonin antagonists), antiulcers (acid pump inhibitors), anti-infectives and antiretroviral agents (grepafloxacin, ornidazole, pefloxacin, stavudine and zidovudine), immunosuppressants (cyclosporin and tacrolimus), naltrexone, tolcapone and toremifene. According to the available data, the kinetics of many drugs are altered by liver disease to an extent that requires dosage adjustment; the problem is to quantify the required changes. Obviously, this requires the evaluation of the degree of hepatic impairment. At present there is no satisfactory test that gives a quantitative measure of liver function and its impairment. A critical evaluation of these methods is provided. Guidelines providing a rational basis for dosage adjustment are illustrated. Finally, it is important to consider that liver disease not only affects pharmacokinetics but also pharmacodynamics. This review also examines drugs with altered pharmacodynamics.