A new herb-drug interaction of Polygonum cuspidatum, a resveratrol-rich nutraceutical, with carbamazepine in rats.
Carbamazepine (CBZ), an antiepileptic with narrow therapeutic window, is a substrate of CYP 3A which metabolizes CBZ to carbamazepine-10,11-epoxide (CBZE), an active metabolite. This study investigated the acute and chronic effects of Polygonum cuspidatum (PC), a resveratrol-rich nutraceutical, on the pharmacokinetics of CBZ in rats and the underlying mechanisms. Rats were orally administered CBZ (200 mg/kg) alone and coadministered with a single dose and the 7th dose of PC (2 g/kg) in a crossover design. The concentrations of CBZ and CBZE in serum and various tissues were determined by HPLC method. The results showed that PC significantly increased the AUC(0-t) of CBZ and CBZE, whereas the formation rate of CBZE was decreased. Tissue analysis showed that the concentrations of CBZ and CBZE in brain, liver and kidney were significantly increased by PC. Cell studies indicated that the efflux function of MRP 2 was inhibited by the serum metabolites of PC. In conclusion, PC markedly increased the systemic exposure and brain concentration of CBZ and CBZE through inhibiting the activities of CYP 3A and MRP 2.
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, 40402, Taiwan.
Ying-Chang
YC
Chi
Shiuan-Pey
SP
Lin
Yu-Chi
YC
Hou
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D045468:Fallopia japonica / Q000737:chemistry*; D041743:Herb-Drug Interactions; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000302:isolation & purification; D014018:Tissue Distribution
D000927:Anticonvulsants; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010936:Plant Extracts; D000077185:Resveratrol; D013267:Stilbenes; C012227:carbamazepine epoxide