PT  - JOURNAL ARTICLE
AU  - Kazuto Yasuda
AU  - Lu-bin Lan
AU  - Dominique Sanglard
AU  - Katryn Furuya
AU  - John D. Schuetz
AU  - Erin G. Schuetz
TI  - Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein
AID  - 10.1124/jpet.102.037549
DP  - 2002 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 323--332
VI  - 303
IP  - 1
4099  - http://jpet.aspetjournals.org/content/303/1/323.short
4100  - http://jpet.aspetjournals.org/content/303/1/323.full
SO  - J Pharmacol Exp Ther2002 Oct 01; 303
AB  - Many clinically important drug interactions occur due to inhibition of human liver cytochrome P450 3A (CYP3A) metabolism. The drug efflux pump P-glycoprotein (Pgp) can be an additional locus contributing to these drug interactions because there is overlap in drugs that are substrates for both proteins. We screened a number of CYP3A inhibitors (macrolide antibiotics, azole antifungals, and ergotpeptides) for their ability to interact with Pgp, compared with prototypical Pgp inhibitors. We used cell lines expressing human, mouse, and rat mdr1 genes. Pgp antagonism was defined by interactions of the drugs with four cell lines (LLC-PK1, L-MDR1, L-mdr1a, and L-mdr1b) using a microfluorometric calcein-AM assay and characterized for their inhibitor constant (Ki) toward calcein-AM. The compounds were further defined for their ability to inhibit MDR1 by their effect on vinblastine accumulation into L-MDR1 cells. Representative compounds from each class of drugs were further tested as Pgp substrates, defined by the ability of human Pgp or mouse mdr1a/Pgp to transport them across a polarized kidney epithelial cell in vitro. These same compounds were administered radiolabeled in vivo to mdr1a (+/+) and (−/−) mice and the distribution of radioactivity compared. The results are summarized as follows: 1) Some drug interactions with Pgp were substrate- and/or assay-dependent. 2) Ergot alkaloids were identified as a class of MDR1/Pgp chemosensitizers. 3) The Ergot alkaloids revealed species differences in the structure-activity relationships for inhibition of Pgp. Simultaneous inhibition of Pgp by many CYP3A inhibitors contributes to human variation in the extent of drug-drug interactions. The American Society for Pharmacology and Experimental Therapeutics