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

Masahiro Iwaki1, Toshiro Niwa2, Hiroyuki Tanaka3, Atsushi Kawase3, Hiroshi Komura3

1Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan. Pharmaceutical Research and Technology Institute, Kindai University, Osaka, Japan. Antiaging Center, Kindai University, Osaka, Japan.
2Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan. School of Pharmacy, Shujitsu University, Okayama, Japan
3Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan.


Hepatic clearance (CLh) 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 (CLtot) of S-CAR were approximately two times greater than those of R-CAR in both strains. CLh predicted from in vitro studies using DA rat liver microsomes was different from that obtained from in vivo studies. In contrast, in vitro CLh prediction using DA rat hepatocytes was nearly identical to the CLh observed in DA rats in vivo, and was lower than that in SD rats. The predicted CLhin vitro using hepatocytes correlated well with the observed CLtot in vivo, which is expected to be nearly the same as CLh. These results suggest that in vitro metabolic studies using hepatocytes are more relevant with regard to stereoselectively predicting CLh of CAR than those using liver microsomes.

J Pharm Pharm Sci, 22 (1): 72-84, 2019

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