Hepatic drug metabolism in rats with experimental chronic renal failure.

The activities of several hepatic microsomal, mitochondrial, and cytosolic drug-metabolizing enzymes, as well as the components of the cytochrome P-450 system, were determined in vitro for control, sham-operated, and uremic rats. Chronic renal failure (CRF) was produced by a two-stage surgical procedure. In this model, the animals were maintained for 21 days postoperatively before assay. During this time, serum urea nitrogen (SUN) levels rose from control levels of 21 mg/dl to an average of 63 mg/dl. Enzymes assayed included microsomal N-, O-, and S-demethylases, esterase, and UDP-glucuronyl transferase; monoamine oxidase; and alcohol dehydrogenase. CRF caused decreases of 24-32% in N- and O-demethylase activities, while S-demethylase, esterase, UDP-glucuronyl transferase, and monoamine oxidase activities were not altered significantly. Alcohol dehydrogenase activity was increased 71%. In addition, the functional components of the microsomal mixed-function oxidase system were assayed. CRF caused a 26% decrease in cytochrome P-450 levels, as compared to sham-operated controls, but cytochrome b5 and NADPH-cytochrome c (P-450) reductase were not altered. CRF caused an increase in hexobarbital sleeping time of more than 7-fold. In each case, alterations in enzyme activities or cytochrome P-450 correlated with the extent of renal failure, as determined by elevated SUN levels.