Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein

Abstract

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 (K i ) 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 (ϩ/ϩ) and (Ϫ/Ϫ) 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 structureactivity relationships for inhibition of Pgp. Simultaneous inhibition of Pgp by many CYP3A inhibitors contributes to human variation in the extent of drug-drug interactions.

Impact of Curcumin-Induced Changes in P-Glycoprotein and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats

“…The overlapping tissue distribution of CYP3A and P-gp, as well as the broad spectrum of drugs that interact with both proteins, has presented significant challenges to drug absorption and delivery to the systemic circulation (Yasuda et al, 2002). Moreover, the interaction of coadministered drugs with CYP3A and P-gp in the gut can lead to major drug-drug interactions (Yasuda et al, 2002).…”

“…Moreover, the interaction of coadministered drugs with CYP3A and P-gp in the gut can lead to major drug-drug interactions (Yasuda et al, 2002). Given the substantial overlaps in substrate, inducer, and inhibitor specificities between the P-gp and CYP3A, it is important to understand the relative contribution of CYP3A and P-gp to specific drug interactions (Wacher et al, 1995;Yasuda et al, 2002).…”

Pharmacogenetics of Antiparkinsonian Drug Treatment: A Systematic Review

“…P-glycoprotein, encoded by the multidrug resistance 1 gene, is implicated in transport of substances, such as drugs, out of the brain and in the small intestine. The ergot-alkaloid bromocriptine is found to be an inhibitor of P-glycoprotein [83]. Moreover, budipine is shown to be transported from the brain by P-glycoprotein in mice [84].…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…Fluconazole Potent inhibitor of CYP2C9 and CYP2C19, 44,45 and less so for CYP3A4. 160 No inhibition of P-gp [160][161][162] or BCRP. 163 Interaction with ciclosporin via CYP inhibition causes increased ciclosporin levels, especially with oral fluconazole.…”