Renal disease and drug metabolism: an overview

Renal disease will perturb the disposition of drugs that primarily depend upon renal excretory function for elimination. While changes in drug half-life (T1/2) are often cited as evidence of altered drug disposition, it must be remembered that T1/2 is a dependent variable whose magnitude varies directly with volume of distribution (Vd) and indirectly with total body clearance (ClT). ClT is the one term that succinctly describes drug elimination. ClT is defined as the sum of the renal (ClR) and nonrenal (ClNR), or metabolic, clearances of a drug. Renal failure has been shown to alter the hepatic microsomal mixed-function oxidase system of drug metabolizing enzymes. Therefore, in end-stage renal failure, the potential exists for the modification of the disposition of drugs whose elimination is primarily hepatic. The kidneys themselves contain many of the enzymes important in hepatic drug metabolism. Drugs such as morphine, paracetamol, and p-aminobenzoic acid are metabolized in the kidney and experimental renal disease has been shown to reduce drug metabolism in the diseased kidney compared with the contralateral normal kidney. Renal disease, then, has the potential to alter not only the renal clearance of unchanged drug but also may substantially modify the metabolic transformation of drugs in both the liver and the kidneys. It can no longer be assumed that the pharmacokinetics of drugs that are disposed mainly by metabolism will be unaltered in renal failure.