P-glycoprotein is a factor in the uptake of dextromethorphan,but not of melperone,into the mouse brain: evidence for an overlap in substrate specificity between P-gp and CYP2D6

Abstract

In this study, the role of P-glycoprotein (P-gp) for the pharmacokinetics of dextromethorphan, a CYP2D6 substrate, and of melperone, a CYP206 inhibitor, was investigated. The substances were administered subcutaneously near the nape of the neck of wild-type mice and of abcb1ab (–/–) mice. One hour after injection, concentrations of the two drugs in cerebrum, plasma and in different organs were measured by high-performance liquid chromatography. No significant differences between wild-type mice and abcb1ab (–/–) mice were observed for melperone, suggesting that P-gp is not involved in the uptake of melperone into the brain or other organs of mice. The concentration of dextromethorphan in the brain was more than twice as high in abcb1ab (–/–) mice compared to wild-type mice. Therefore, P-gp appears to be a factor in the uptake of dextromethorphan into the mouse brain, and abcb1-polymorphisms need to be considered for CYP2D6 phenotyping experiments with this drug. There is an overlap in substrate specificity between P-gp and CYP2D6. P-gp is a factor in the uptake of dextromethorphan, but not of melperone.