CYP3A5 polymorphism affects the disposition of tacrolimus and its metabolite in systemic circulation and peripheral tissues of mice introduced with the CYP3A5 gene

Abstract

The CYP3A5∗3 allele, which leads to a splicing defect resulting in the absence of the CYP3A5 protein, is the prevalent variant in most populations. Tacrolimus dose is individualized for each patient because the CYP3A5 polymorphism impacts its pharmacokinetics. Despite tacrolimus blood levels remaining within the narrow therapeutic index, some patients still experience adverse effects associated with the CYP3A5 polymorphism. Therefore, not only systemic disposition but also peripheral metabolism of tacrolimus in each tissue is considered to understand the mechanism of its adverse effects. Here, we assess the distribution of tacrolimus and its metabolite in liver, kidney, and lung using a CYP3A-humanized mouse model with CYP3A5∗1 or CYP3A5∗3. The expression of CYP3A5 and formation of desmethyl tacrolimus were found in the liver, intestine, kidney, and lung of CYP3A5∗1 mice. When the mice were orally dosed with 3 mg/kg tacrolimus, CYP3A5∗1 mice showed lower levels of tacrolimus and higher levels of desmethyl tacrolimus in their liver, kidney, and lung compared with CYP3A5∗3 mice. Furthermore, the desmethyl tacrolimus-to-tacrolimus level ratios in CYP3A5∗1 mice were higher than those in CYP3A5∗3 mice, especially in the kidney. These findings suggest that tacrolimus is metabolized in peripheral tissues expressing CYP3A5, resulting in the elevation of desmethyl tacrolimus levels in those tissues. In conclusion, we suggest the differential disposition of tacrolimus and desmethyl tacrolimus in peripheral tissues related to CYP3A5 polymorphism by using the unique mouse models carrying CYP3A5∗1 and CYP3A5∗3. SIGNIFICANCE STATEMENT: CYP3A5 was expressed in several peripheral tissues of the CYP3A5∗1 mice generated using a mammalian artificial chromosome vector. Differential disposition of tacrolimus and its metabolite was found in the tissues of CYP3A5∗1 and CYP3A5∗3 mice. This model would be a promising tool to reveal CYP3A5-mediated drug metabolism in peripheral tissues.

Keywords: CYP3A5; Extrahepatic metabolism; Humanized mouse model; Tacrolimus.