Prediction of Hepatic Clearance of Stereoselective Metabolism of Carvedilol in Liver Microsomes and Hepatocytes of Sprague-Dawley and Cytochrome P450 2D-Deficient Dark Agouti Rats

Hepatic clearance ( CL h ) of carvedilol (CAR), which is eliminated via stereoselective metabolism by the CYP2D subfamily of cytochromes P450 (CYPs), was predicted using liver microsomes and hepatocytes from Sprague-Dawley (SD) rats and CYP2D-deficient Dark Agouti (DA) rats to determine the usefulness of prediction method. Plasma concentrations of CAR following intravenous injection to DA rats were higher than those in SD rats. The volume of distribution at steady state and total clearance ( CL tot ) of S -CAR were approximately two times greater than those of R -CAR in both strains. CL h predicted from in vitro studies using DA rat liver microsomes was different from that obtained from in vivo studies. In contrast, in vitro CL h prediction using DA rat hepatocytes was nearly identical to the CL h observed in DA rats in vivo , and was lower than that in SD rats. The predicted CL h in vitro using hepatocytes correlated well with the observed CL tot in vivo , which is expected to be nearly the same as CL h . These results suggest that in vitro metabolic studies using hepatocytes are more relevant with regard to stereoselectively predicting CL h of CAR than those using liver microsomes.