Evaluation of the flavonoid oroxylin A as an inhibitor of P-glycoprotein-mediated cellular efflux.
Oroxylin A (1), a flavonoid from the roots of Scutellaria baicalensis, increased the cellular accumulation of calcein AM in a concentration-dependent manner in NCI/ADR-RES cells overexpressing P-glycoprotein over the concentration range 0-40 microM. In addition, 1 significantly (p < 0.05) increased the cellular accumulation of paclitaxel in NCI/ADR-RES cells while it did not alter the cellular accumulation of paclitaxel in cells lacking P-glycoprotein expression. Accordingly, the concentrations that yielded 50% cytotoxicity of vinblastine and paclitaxel were reduced by approximately 5-fold in the presence of 1. This indicated that cancer cells became more susceptible to the cytotoxicity of vinblastine and paclitaxel in the presence of 1. The concomitant use of 1 (30 mg.kg(-1)) significantly (p < 0.05) enhanced the oral exposure of paclitaxel (15 mg.kg(-1)) in rats. The C(max) and AUC values of paclitaxel increased by 2.1-2.6-fold in the presence of 1 with no significant change in T(max). In conclusion, 1 was effective in inhibiting P-glycoprotein-mediated drug efflux both in vitro and in vivo, suggesting that it may be useful to improve the cellular availability of P-glycoprotein substrates such as anticancer drugs.
Go
Woon Jung
WJ
BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, Korea.
Ryu
Jong Hoon
JH
Qiang
Fu
F
Han
Hyo-Kyung
HK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D051381:Rats; D031364:Scutellaria baicalensis / Q000737:chemistry; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005419:Flavonoids; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D014747:Vinblastine; D017239:Paclitaxel