Mdr1 limits CYP3A metabolism in vivo

We determined whether the drug efflux protein P-glycoprotein (Pgp) could in fluence the extent of CYP3A-mediated metabolism of erythromycin, a widely u sed model substrate for CYP3A. We compared CYP3A metabolism of erythromycin (a Pgp substrate) using the erythromycin breath test in mice proficient an d deficient of mdr1 drug transporters. We first injected mdr1(+/+) mice wit h [C-14]N-methyl erythromycin and measured the rate of appearance of (CO2)- C-14 in the breath as a measure of hepatic CYP3A activity. Animals treated with CYP3A inducers or inhibitor showed accelerated or diminished (CO2)-C-1 4 in the breath, respectively. The erythromycin breath test was next admini stered to mdr1a(-/-) and mdr1a/1b(+/+) and (-/-) mice. These animals had eq uivalent levels of immunoreactive CYP3A and CYP3A activity as measured by e rythromycin N-demethylase activity in liver microsomes. Nevertheless, the r ate of (CO2)-C-14 appearance in the breath showed no relationship with thes e measurements of CYP3A, but changed proportionally to expression of mdr1. The average breath test (CO2)-C-14 area under the curves were 1.9- and 1.5- fold greater in mdr1a/1b(-/-) and mdr1a(-/-) mice, respectively, compared w ith (+/+) mice, and CERmax was 2-fold greater in mdr1a/1b(-/-) compared wit h (+/+) mice. We conclude that Pgp, by limiting intracellular substrate ava ilability can be an important determinant of CYP3A metabolism of numerous m edications that are substrates for CYP3A and Pgp.