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Description of HM30181: HM30181 is an oral P-glycoprotein (P-gp) inhibitor developed to enhance the oral bioavailability of P-gp substrate drugs. 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). HM30181 is currently under Phase I trials. HM30181 was well tolerated after oral administration within the dose range evaluated, with the exception of the repeated administration of 360 mg, for which gastrointestinal disorders were frequently reported. The systemic exposure of HM30181 was relatively low, and dose proportional properties of HM30181 were not observed.
Current developer: Hanmi Pharmaceutical Company Limited.
HM30181 is a MDR1 inhibitor with 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. (source: Eur J Pharmacol. 2010 Feb 10;627(1-3):92-8. Epub 2009 Nov 10.)
1: Kwak JO, Lee SH, Lee GS, Kim MS, Ahn YG, Lee JH,
Kim SW, Kim KH, Lee MG. Selective inhibition of MDR1 (ABCB1) by HM30181
increases oral bioavailability and therapeutic efficacy of paclitaxel.
Eur J Pharmacol. 2010 Feb 10;627(1-3):92-8. Epub 2009 Nov 10. PubMed
(Keyword; CAS#; MedKoo code#)
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