EFFECTS OF LIVER-DISEASE ON DRUG DISPOSITION IN MAN

Despite the occasional conflicting data, there seems to be little doubt that the hepatic drug elimination for many drugs is impaired in patients with liver disease and that the changes are somewhat less dramatic in acute viral hepatitis than in cirrhosis. The concept that only the intrinsic metabolizing or excretory abilities are affected by liver disease is too simplistic. All of the major determinants of disposition may be altered to varying degrees dependent on the specific drug and disease-state. The use of the elimination half-life to assess the severity of hepatic damage provides little indication of the magnitude or inter-relationship of these processes. Consideration must be given to elucidating and quantifying the alterations in the physiological determinants of the disposition processes, particularly as they affect the systemic and hepatic clearance of both total and unbound drug. Information on liver blood flow, hepatic extraction ratio and intrinsic clearance would reveal the more fundamental aspects of any change in hepatic clearance. A clearer understanding of the unequal effect that liver disease can have upon the hepatic elimination of different drugs and different pathways of metabolism would also be valuable. The various routes of drug metabolism exhibit profoundly different sensitivities to the consequences of liver disease. If the reasons for this were appreciated, this might allow a more rational choice of drug in the treatment of such patients. Empiricism coupled with a good understanding of any pharmacokinetic changes, in drug disposition, remains the basis for the use of drugs in patients with liver disease.