Usefulness of hepatocytes for evaluating the genetic polymorphism of CYP2D6 substrates

Abstract

The usefulness of human hepatocytes for assessing CYP2D6-related genetic polymorphisms was investigated. Propranolol and propafenone, which undergo phase I and II biotransformations, were used as model substrates alongside metoprolol, which is only metabolized via oxidative pathways. The contributions of CYP2D6 to the primary metabolisms of the substrates were estimated from the quinidine-mediated inhibition of their depletion rate constants in human hepatocytes and liver microsomes. The contributions in hepatocytes were 19.2% for propranolol at 0.05 µM and 36.7–76.3% for propafenone at 0.05–1.0 µM, and smaller than the contribution in microsomes, unlike the case for metoprolol. The differences between microsomes and hepatocytes were attributable to conjugate formation. The CYP2D6 contributions in hepatocytes reflected the in vivo data. The relevance of the concentration-dependent involvement of CYP2D6 in propafenone metabolism in hepatocytes to the in vivo polymorphic profile and the applicability of hepatocytes for evaluating these polymorphisms are discussed.