Received for publication January 5, 2005.
Revised May 13, 2005.
Accepted for publication May 16, 2005.

Effects of Dihydropyridines and Pyridines on Multidrug Resistance Mediated by Breast Cancer Resistant Protein: In Vitro and In Vivo Studies

Abstract

Breast cancer resistance protein (BCRP, ABCG2) is a recently identified member of the ABC family of cell surface transport proteins. This study was conducted to investigate the effect of a series of newly synthesized 1,4-dihydropyridines and pyridines, designed as potent P-glycoprotein inhibitors, on BCRP-mediated drug efflux both in vitro and in vivo. The effects of 25 synthesized dihydropyridines and corresponding pyridines along with 4 commercially available dihydropyridines (niguldipine, nicardipine, nifedipine and nitrendipine) on the intracellular accumulation of the BCRP substrate mitoxantrone were evaluated in BCRP-expressing human breast cancer MCF7/MX100 and human non-small lung cancer H460/MX20 cells. At a 2.5 µM concentration, 24 out of 25 newly synthesized dihydropyridines and pyridines produced a significant increase of mitoxantrone accumulation in both cell lines. The most potent compound was able to enhance mitoxantrone accumulation approximately 4.5-fold, greater than that obtained with 10 µM of fumitremorgin C, which is a specific BCRP inhibitor. The results from the two cell lines showed good correlation (r² = 0.71, p<0.01). Niguldipine, nicardipine and nitrendipine also demonstrated potent BCRP inhibition, while nifedipine had no effect. The effects of the dihydropyridine and pyridine compounds on mitoxantrone cytotoxicity paralleled their effects on mitoxantrone accumulation. Co-administration of a selected dihydropyridine compound, I_m (DHP-014) with topotecan, a good BCRP substrate and a moderate to poor P-glycoprotein substrate, resulted in significant increases in the systemic exposure and peak concentration of topotecan in Sprague-Dawley rats when oral topotecan 2 mg/kg was combined with 20 mg/kg DHP-014. The observed increase of topotecan exposure provides proof-of-concept for in vivo inhibition of BCRP by these agents.

Key words: ABC transporters, drug transport, drug-drug interactions, membrane transport, multi-drug resistance, pharmacokinetics