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

doi:10.1016/j.ejphar.2009.11.008

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. doi: 10.1016/j.ejphar.2009.11.008. Epub 2009 Nov 10.

Authors

Jin-Oh Kwak¹, Sung Hee Lee, Gwan Sun Lee, Maeng Sup Kim, Young-Gil Ahn, Ji Hyun Lee, So Won Kim, Kyung Hwan Kim, Min Goo Lee

Affiliation

¹ 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.

PMID: 19903471
DOI: 10.1016/j.ejphar.2009.11.008

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP-Binding Cassette Transporters / metabolism
Administration, Oral
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacokinetics*
Antineoplastic Agents / therapeutic use*
Benzopyrans / administration & dosage
Benzopyrans / pharmacology*
Biological Availability
Cell Line
Colonic Neoplasms / drug therapy
Colonic Neoplasms / metabolism
Colonic Neoplasms / therapy
Dogs
Humans
Isoquinolines / administration & dosage
Isoquinolines / pharmacology*
Male
Mice
Multidrug Resistance-Associated Protein 2
Paclitaxel / administration & dosage
Paclitaxel / pharmacokinetics*
Paclitaxel / therapeutic use*
Rats
Rats, Sprague-Dawley
Substrate Specificity
Tetrazoles / administration & dosage
Tetrazoles / pharmacology*
Treatment Outcome
Xenograft Model Antitumor Assays

Substances

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
ABCC2 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP-Binding Cassette Transporters
Antineoplastic Agents
Benzopyrans
Isoquinolines
Multidrug Resistance-Associated Protein 2
Tetrazoles
Paclitaxel