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Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel.

 Jin-Oh Kwak  ;  Sung Hee Lee  ;  Gwan Sun Lee  ;  Maeng Sup Kim  ;  Young-Gil Ahn  ;  Ji Hyun Lee  ;  So Won Kim  ;  Kyung Hwan Kim  ;  Min Goo Lee 
 European Journal of Pharmacology, Vol.627(1-3) : 92-98, 2010 
Journal Title
 European Journal of Pharmacology 
Issue Date
Multi-drug resistance 1 (MDR1, ABCB1), also known as P-glycoprotein (P-gp), restricts intestinal uptake of many drugs, and contributes to cellular resistance to cancer chemotherapy. In this study, we examined the pharmacologic characteristics of HM30181, a newly developed MDR1 inhibitor, and tested its capacity to increase the oral bioavailability and efficacy of paclitaxel, an anti-cancer drug usually given by intravenous injection. In the ATPase assay using MDR1-enriched vesicles, HM30181 showed the highest potency (IC(50)=0.63nM) among several MDR1 inhibitors, including cycloporin A, XR9576, and GF120918, and effectively blocked transepithelial transport of paclitaxel in MDCK monolayers (IC(50)=35.4nM). The ATPase inhibitory activity of HM30181 was highly selective to MDR1. HM30181 did not inhibit MRP1 (ABCC1), MRP2 (ABCC2), and MRP3 (ABCC3), and partially inhibited BCRP (ABCG2) only at very high concentrations. Importantly, co-administration of HM30181 (10mg/kg) greatly increased oral bioavailability of paclitaxel from 3.4% to 41.3% in rats. Moreover, oral co-administration of paclitaxel and HM30181 showed a tumor-inhibitory strength equal or superior to that of intravenous paclitaxel in the xenograft model in nude mice. These results identify HM30181 as a highly selective and potent inhibitor of MDR1, which in combination with paclitaxel, may provide an orally effective anti-tumor regimen.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
곽진오(Kwak, Jin Oh)
김경환(Kim, Kyung Hwan)
김소원(Kim, So Won)
이민구(Lee, Min Goo) ORCID logo https://orcid.org/0000-0001-7436-012X
이성희(Lee, Sung Hee)
이지현(Lee, Ji Hyun)
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