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• W1870564186 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 of<i>mdr1</i> drug transporters. We first injected<i>mdr1</i>(+/+) mice with [¹⁴C]<i>N</i>-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 to<i>mdr1a</i>(−/−) and <i>mdr1a/1b</i>(+/+) and (−/−) mice. These animals had equivalent levels of immunoreactive CYP3A and CYP3A activity as measured by erythromycin<i>N-</i>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 <i>mdr1a/1b</i>(−/−) and<i>mdr1a</i>(−/−) mice, respectively, compared with (+/+) mice, and CER_max was 2-fold greater in<i>mdr1a/1b</i>(−/−) 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." @default.
• W1870564186 created "2016-06-24" @default.
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• W1870564186 date "2000-10-01" @default.
• W1870564186 modified "2023-10-14" @default.
• W1870564186 title "<i>Mdr1</i> Limits CYP3A Metabolism in Vivo" @default.
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• W1870564186 doi "https://doi.org/10.1124/mol.58.4.863" @default.
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