Propranolol is a mechanism-based inhibitor of CYP2D and CYP2D6 in humanized CYP2D6-transgenic mice: Effects on activity and drug responses.

ABSTRACT:

Background and purpose

Genetics and drug interactions contribute to large interindividual variation in human CYP2D6 activity. Here, we have characterized propranolol inhibition of human and mouse CYP2D using transgenic (TG) mice, which express both mouse CYP2D and human CYP2D6, and wild-type (WT) mice. Our purpose was to develop a method for in vivo manipulation of CYP2D6 enzyme activity which could be used to investigate the role of CYP2D6 in drug-induced behaviours.

Experimental approach

Dextromethorphan metabolism to dextrorphan was used to measure CYP2D activity and to characterize propranolol inhibition in vitro and in vivo. Effects of propranolol pretreatment (24 hr) on serum levels of the CYP2D6 substrate haloperidol and haloperidol-induced catalepsy were also studied.

Key results

Dextrorphan formation velocity in vitro was threefold higher in liver microsomes of TG compared to WT mice. Propranolol acted as a mechanism-based inhibitor (MBI), inactivating CYP2D in liver microsomes from TG and WT mice, and humans. Pretreatment (24 hr) of TG and WT mice with 20 mg·kg^-1 intraperitoneal propranolol reduced dextrorphan formation in vivo and by liver microsomes in vitro. Serum haloperidol levels and catalepsy were increased.

Conclusions and implications

Propranolol was a potent MBI of dextrorphan formation in liver microsomes from TG and WT mice, and humans. The inhibition parameters in TG overlapped with those in WT mice and in humans. Inhibition of CYP2D with propranolol in vivo in TG and WT mice altered drug responses, allowing further investigation of variations in CYP2D6 on drug interactions and drug responses.

SUBMITTER: Tolledo EC 

PROVIDER: S-EPMC7012948 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature