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

Authors

  • Masahiro Iwaki Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan. Pharmaceutical Research and Technology Institute, Kindai University, Osaka, Japan. Antiaging Center, Kindai University, Osaka, Japan.
  • Toshiro Niwa Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan. School of Pharmacy, Shujitsu University, Okayama, Japan
  • Hiroyuki Tanaka Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan.
  • Atsushi Kawase Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan.
  • Hiroshi Komura Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan.

DOI:

https://doi.org/10.18433/jpps30237

Abstract

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 CLh in 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.

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Published

2019-01-24

How to Cite

Iwaki, M., Niwa, T., Tanaka, H., Kawase, A., & Komura, H. (2019). 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. Journal of Pharmacy & Pharmaceutical Sciences, 22(1), 72–84. https://doi.org/10.18433/jpps30237

Issue

Vol. 22 (2019): Pages 1 - 130

Section

Pharmaceutical Sciences; Original Research Articles

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