Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats.
Isoflavone supplements are nowadays widely used as alternative for hormone replacement therapy. However, the safety remains unanswered. This study attempted to investigate the effect of Pueraria lobata root decoction (PLRD), an isoflavone-rich herb, on the pharmacokinetics of methotrexate (MTX), a bicarboxylate antimetabolite with narrow therapeutic window. Rats were orally and intravenously given methotrexate alone and coadministered with PLRD. Blood samples were withdrawn via cardiopuncture at specific time points after drug administration. Serum methotrexate concentrations were assayed by specific monoclonal fluorescence polarization immunoassay method. Pharmacokinetic parameters were calculated using noncompartment model of WINNONLIN for both oral and intravenous data of MTX. Our results showed that coadministration of 4.0 g/kg and 2.0 g/kg of PLRD significantly increased the AUC(0-t) by 207.8% and 127.9%, prolonged the mean residence time (MRT) by 237.8 and 155.2%, respectively, finally resulted in surprisingly high mortalities of 57.1% and 14.3% in rats. When MTX was given intravenously, the coadministration of PLRD at 4.0 g/kg significantly increased the half-life by 53.9% and decreased the clearance by 47.9%. In conclusion, the coadministration of PLRD significantly decreased the elimination and resulted in markedly increased exposure of MTX in rats.
Chiang
Hsiu-Mei
HM
Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan, ROC.
Fang
Shih-Hua
SH
Wen
Kuo-Ching
KC
Hsiu
Su-Lan
SL
Tsai
Shang-Yuan
SY
Hou
Yu-Chi
YC
Chi
Ying-Chang
YC
Chao
Pei-Dawn Lee
PD
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001247:Asthenia / Q000139:chemically induced; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D041743:Herb-Drug Interactions; D007275:Injections, Intravenous; D007529:Isoflavones / Q000032:analysis / Q000737:chemistry; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015394:Molecular Structure; D010863:Piloerection / Q000187:drug effects; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry*; D029908:Pueraria / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007529:Isoflavones; D010936:Plant Extracts; D008727:Methotrexate