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Pharm Res. 2008 Oct;25(10):2320-6. doi: 10.1007/s11095-008-9632-1. Epub 2008 Jun 4.

Characterization of substrates and inhibitors for the in vitro assessment of Bcrp mediated drug-drug interactions.

Author information

1
Department of Metabolism and Pharmacokinetics, Bayer HealthCare AG, Aprather Weg, 42096, Wuppertal-Aprath, Germany.

Abstract

PURPOSE:

In vitro assessment of drug candidates' affinity for multi-drug resistance proteins is of crucial importance for the prediction of in vivo pharmacokinetics and drug-drug interactions. To have well described experimental tools at hand, the objective of the study was to characterize substrates and inhibitors of Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp).

METHODS:

Madin-Darbin canine kidney cells overexpressing mouse Bcrp (MDCKII-Bcrp) were incubated with various Bcrp substrates, or a mixture of substrate and inhibitor to either the apical (A) or basolateral (B) compartment of insert filter plates. Substrate concentrations in both compartments at time points t = 0 h and t = 2 h were determined by LC-MS/MS, and respective permeation coefficients (Papp) and efflux ratios were calculated.

RESULTS:

The Bcrp inhibitor Ko143 blocked topotecan and ABZSO transport in a concentration-dependent manner. P-gp inhibitors ivermectin, LY335979, PSC833, and the P-gp/Bcrp inhibitor ritonavir did not influence Bcrp mediated topotecan transport, however, blocked ABZSO transport. Additionally, neither was ABZSO transport influenced by topotecan, nor topotecan transport by ABZSO.

CONCLUSIONS:

Data suggest different modes of substrate and inhibitor binding to Bcrp. In order to not overlook potential drug-drug interactions when testing drug candidates for inhibitory potential towards Bcrp, distinct Bcrp probe substrates should be used.

PMID:
18523872
DOI:
10.1007/s11095-008-9632-1
[Indexed for MEDLINE]

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