Mdr1 Limits CYP3A Metabolism in Vivo

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Abstract
We determined whether the drug efflux protein P-glycoprotein (Pgp) could influence the extent of CYP3A-mediated metabolism of erythromycin, a widely used model substrate for CYP3A. We compared CYP3A metabolism of erythromycin (a Pgp substrate) using the erythromycin breath test in mice proficient and deficient ofmdr1 drug transporters. We first injectedmdr1(+/+) mice with [14C]N-methyl erythromycin and measured the rate of appearance of 14CO2 in the breath as a measure of hepatic CYP3A activity. Animals treated with CYP3A inducers or inhibitor showed accelerated or diminished14CO2 in the breath, respectively. The erythromycin breath test was next administered tomdr1a(−/−) and mdr1a/1b(+/+) and (−/−) mice. These animals had equivalent levels of immunoreactive CYP3A and CYP3A activity as measured by erythromycinN-demethylase activity in liver microsomes. Nevertheless, the rate of 14CO2 appearance in the breath showed no relationship with these measurements of CYP3A, but changed proportionally to expression of mdr1. The average breath test14CO2 area under the curves were 1.9- and 1.5-fold greater in mdr1a/1b(−/−) andmdr1a(−/−) mice, respectively, compared with (+/+) mice, and CERmax was 2-fold greater inmdr1a/1b(−/−) compared with (+/+) mice. We conclude that Pgp, by limiting intracellular substrate availability can be an important determinant of CYP3A metabolism of numerous medications that are substrates for CYP3A and Pgp.

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