Dmd050302 1398..1403

Wuzhi capsule (WZC) is a preparation of an ethanol herbal extract of Schisandra sphenanthera (Nan-Wuweizi), with its main active ingredients that include schisandrin, schizandrol B, schisantherin A, schisanhenol, and deoxyschizandrin. WZC and tacrolimus are often coadministered for the treatment of drug-induced hepatitis in organ transplant recipients in China. Recently, it was reported that WZC could significantly increase the blood concentration of tacrolimus. The purpose of this study was to investigate whether and how WZC affects the pharmacokinetics of tacrolimus in rats. Liquid chromatography–tandem mass spectrometry method was used to determine the plasma concentration of tacrolimus. The results showed that WZC increased the mean plasma concentration of tacrolimus. Compared with administration of tacrolimus alone [maximum plasma concentration (Cmax), 18.87 6 10.29 ng/ml; area under the plasma concentration–time curve from time zero to last sampling time (AUC0→t), 40.98 6 37.07 ng h/ml], a single intragastric administered dose of WZC increased the pharmacokinetic parameters of tacrolimus (Cmax, 59.42 6 30.32 ng/ml; AUC0→t, 239.71 6 28.86 ng h/ml) by 5-fold in rat plasma. After pretreatment with WZC for 12 days, there were still significant increases in AUC0→t (from 40.98 6 37.07 to 89.21 6 26.39 ng h /ml; P < 0.05) and Cmax (from 18.87 6 10.29 to 43.16 6 10.61 ng/ml; P < 0.05) of tacrolimus, compared with oral of tacrolimus alone, suggesting that WZC increased the exposure of tacrolimus by one or more mechanisms. The increase in tacrolimus Cmax by WZC was dosedependent. The effect of WZC on tacrolimus AUC0→t also increased with dose, with a maximal effect observed at 450 mg/kg (825.34 ng h/ml). No further increases in tacrolimus AUC0→t were observed at WZC dose above 450 mg/kg. It is suggested that, because of the effect of WZC on the pharmacokinetics of tacrolimus, the herbdrug interaction between WZC and tacrolimus should be taken into consideration in clinical practice.