Effects of Traditional Herbal Formulae on Human CYP450 Isozymes

Objective：To assess the effects of traditional herbal formulae Sijunzi Decoction（四君子汤,Sagunja-tang,SJZD）,Siwu Decoction（四物汤,Samul-tang,SWD）,Bawu Decoction（八物汤,Palmul-tang,BWD）and Shiquan Dabu Decoction（十全大补汤,Sipjeondaebo-tang,SDD）on the activities of human cytochrome P450（CYP450）,a drug-metabolizing enzyme.Methods：Herbal formula water extracts were filtered and lyophilized after the powder extracts were dissolved in distilled water.The activities of major human CYP450isozymes（CYP3A4,CYP2C19,CYP2D6 and CYP2E1）were measured using in vitro fluorescence-based enzyme assays.The inhibitory effects of the herbal formulas on the activities of CYP450 were characterized as half maximal inhibition concentration（IC50）values.Results：All the tested herbal formulae inhibited CYP2C19activity（IC50：SJZD,83.28μg/m L;SWD,235.54μg/m L;BWD,166.82μg/m L;SDD,178.19μg/m L）;SJZD（IC50=196.46μg/m L）,SWD（IC50=333.42μg/m L）and SDD（IC50=163.42μg/m L）inhibited CYP2E1-mediated metabolism;whereas BWD exhibited comparatively weak inhibition of CYP2E1（IC50=501.78μg/m L）.None of the four herbal formulas significantly affected CYP3A4 or CYP2D6.Conclusions：These results suggest that SJZD,SWD,BWD and SDD could potentially inhibit the metabolism of co-administered synthetic drugs whose primary route of elimination is via CYP2C19.In addition,clinically relevant pharmacokinetic interactions could occur when SJZD,SWD or SDD is co-administered with drugs metabolized by CYP2E1.Our findings provide information for the safety and effective clinical use of these four classic herbal formulas.

Alterations of Gefitinib Pharmacokinetics by Co-administration of Herbal Medications in Rats

Objective： To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib （Iressae） and the oriental medications Guipi Decoction （归脾汤, GPD, Guibi-tang in Korean） and Bawu Decoction （八物汤, BWD, Palmul-tang in Korean）. Methods： Methylceliulose （MC, control）, GPD （1,200 mg/kg）, or BWD （6,000 mg/kg） was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib （10 mg/kg） was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefltinib （10 mg/kg） was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis. Results： Gefitinib was rapidly absorbed and showed a mono- exponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration （Crux, P〈0.05） and area under the curve （P〈0.05）, and a delayed time to reach Cmax （Tmax, P〈0.01） were observed in both single- and multiple- dose BWD-pretreated rats compared with the control rats. Conclusions： BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.