Pharmacokinetics and Metabolism of Metoprolol and Propranolol in the Female DA and Female Wistar Rat: The Female DA Rat Is Not Always an Animal Model for Poor Metabolizers of CYP2D6

Abstract

The purpose of this study was to clarify the pharmacokinetics of CYP2D6 substrates in female DA and Wistar rats, which are regarded as animal models of poor metabolizers and extensive metabolizers, respectively. In vivo pharmacokinetic and in vitro metabolic studies were conducted using metoprolol and propranolol, which show substantial and marginal polymorphisms in humans, respectively. After oral administration, the areas under the plasma concentration curves (AUC) for metoprolol and propranolol in DA rats were ca. 5- and 35-fold higher, respectively, than those in Wistar rats. There were no strain differences for serum protein binding or metabolism inhibition by quinine between the two compounds. Using a substrate depletion assay, the intrinsic clearances estimated for the two strains differed by 7.2-fold for metoprolol and 4.5-fold for propranolol. The discrepancy between the in vitro and in vivo profiles observed for propranolol, but not metoprolol, would be due to nonlinearity between the normalized AUC and the oral doses in DA rats, being associated with lower Km values. The larger strain difference in the AUCs of propranolol was proved by the in vitro kinetic parameters, implying that DA rats do not always reflect the polymorphic profiles in humans.