title: Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel.
abstract: 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.
authors.affiliation: Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Institute of Gastroenterology, Yonsei University College of Medicine, 134 Sinchon-Dong, Seoul 120-752, Republic of Korea.
authors.forename: Jin-Oh
authors.initials: JO
authors.lastname: Kwak
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Gwan Sun
authors.initials: GS
authors.lastname: Lee
authors.forename: Maeng Sup
authors.initials: MS
authors.lastname: Kim
authors.forename: Young-Gil
authors.initials: YG
authors.lastname: Ahn
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: So Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy; D004285:Dogs; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C521083:4-oxo-4H-chromene-2-carboxylic acid (2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)-phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl)amide; C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001578:Benzopyrans; D007546:Isoquinolines; D000089762:Multidrug Resistance-Associated Protein 2; D013777:Tetrazoles; D017239:Paclitaxel