The effect of renal failure on hepatic drug clearance.

It is known that loss of renal function decreases the hepatic clearance of some drugs, but the mechanisms by which this occurs are unclear. Knowledge of which drugs display reduced hepatic metabolism may be important for appropriate dosing of these drugs in uremic patients. Although no firm conclusions can be made regarding common pharmacokinetic and metabolic characteristics of drugs that display decreased hepatic metabolism in renal failure, certain observations deserve consideration. It appears that drugs metabolized by oxidation, conjugation, or both may be predisposed to decreased hepatic clearance in renal failure. Drugs that undergo oxidation by the P-450IID6 isozyme may be more likely to exhibit inhibition whereas those metabolized by the P-450IIIA4 isozyme may be spared. Future studies designed to clarify the mechanisms of decreased hepatic clearance in renal failure should take into account the multiplicity of P-450 enzymes for drugs that are oxidatively metabolized. The phenomenon of reduced hepatic drug clearance in uremia should be considered when evaluating the influence of renal failure on drug disposition.