Pharmacokinetic interactions between Japanese traditional kampo medicine and modern medicine (IV). Effect of kamisyoyosan and tokisyakuyakusan on the pharmacokinetics of etizolam in rats

Kamisyoyosan (KSS) and Tokisyakuyakusan (TSS) are widely used herbal formulas in Japanese traditional kampo medicine to relieve the symptoms occurred in climacteric disturbance. Since Japanese physicians frequently prescribe these formulas combined with etizolam, one of benzodiazepine anxiolytics, we evaluated the pharmacokinetic interaction between KSS or TSS and etizolam, and in vitro inhibitory effect of KSS and TSS on rat cytochrome P450 (CYP) 3A activity in rat microsomes, to obtain drug information to prevent from disadvantage or adverse effects by their combined therapy. In in vitro experiment, KSS and TSS inhibited CYP3A activity comparable to grapefruit juice. However in in vivo experiments, oral administration of KSS did not influence the plasma concentration profile of etizolam. The maximum concentration (C-max)of etizolam was significantly reduced when TSS was co-administered at 20 times amount of human daily dosage. Since the double of human daily dose of TSS did not suppress the absorption of etizolam, TSS would not influence the pharmacokinetics of etizolam at the usual clinical dosage. Since both KSS and TSS did not influence the metabolism of etizolam, the result of in vitro experiment would not reflect to that of in vivo experiment or in clinic. The combination of etizolam with KSS or TSS at usual dosage would not cause drug interaction.