Physiologically Based Pharmacokinetic Modeling of Metoprolol Enantiomers and α-Hydroxymetoprolol to Describe CYP2D6 Drug-Gene Interactions.

ABSTRACT: The beta-blocker metoprolol (the sixth most commonly prescribed drug in the USA in 2017) is subject to considerable drug-gene interaction (DGI) effects caused by genetic variations of the CYP2D6 gene. CYP2D6 poor metabolizers (5.7% of US population) show approximately five-fold higher metoprolol exposure compared to CYP2D6 normal metabolizers. This study aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model to predict CYP2D6 DGIs with metoprolol. The metoprolol (R)- and (S)-enantiomers as well as the active metabolite α-hydroxymetoprolol were implemented as model compounds, employing data of 48 different clinical studies (dosing range 5-200 mg). To mechanistically describe the effect of CYP2D6 polymorphisms, two separate metabolic CYP2D6 path

SUBMITTER: Rudesheim S 

PROVIDER: S-EPMC7763912 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature