The Effect of <i>Yokukansan</i>, a Traditional Herbal Preparation Used for the Behavioral and Psychological Symptoms of Dementia, on the Drug–Metabolizing Enzyme Activities in Healthy Male Volunteers

Abstract

The concomitant use of herb and prescription medications is increasing globally. Herb-drug interactions are therefore a clinically important problem. Yokukansan (YKS), a Japanese traditional herbal medicine, is one of the most frequently used herbal medicines. It is effective for treating the behavioral and psychological symptoms of dementia. We investigated the potential effects of YKS on drug-metabolizing enzyme activities in humans. An open-label repeat-dose study was conducted in 26 healthy Japanese male volunteers (age: 22.7 2.3 years) with no history of smoking. An 8-h urine sample was collected after a 150-mg dose of caffeine and a 30-mg dose of dextromethorphan before and after the administration of YKS (2.5 g, twice a day for 1 week). The activities of cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, xanthine oxidase (XO) and N-acetyltransferase 2 (NAT2) were assessed based on the urinary metabolic indices of caffeine and dextromethorphan, and the urinary excretion ratio of 6β-hydroxycortisol to cortisol. There were no statistically significant differences in the activities of the examined enzymes before or after the 7-d administration of YKS. Although further studies assessing the influence of YKS on the pharmacokinetics and pharmacodynamics of the substrates of the drug-metabolizing enzymes are needed to verify the present results, YKS is unlikely that a pharmacokinetic interaction will occur with concomitantly administered medications that are predominantly metabolized by the CYP1A2, CYP2D6, CYP3A, XO and NAT2.Key words yokukansan (YKS); herb-drug interaction; drug-metabolizing enzyme; Kampo Dementia is a progressive, irreversible illness and is a worldwide health priority that is associated with an increasing public health burden. 1,2) Alzheimer's disease, a neurodegenerative brain disorder, is the most common form of dementia.

Use of a Caco-2 permeability assay to evaluate the effects of several Kampo medicines on the drug transporter P-glycoprotein

“…Furthermore, it has been reported that the inhibitory potential of YKS and RKT against P-gp was low in an ATPase assay [ 28 ] and did not affect the plasma pharmacokinetics of digoxin in mice [ 19 ]. Ito et al [ 19 ] and Soraoka et al [ 29 ] also evaluated the effects of several Kampo medicines on CYP3A, which is known to have considerable overlap in substrate specificity and tissue localization of P-gp [ 30 ], and it has been reported that the inhibition rate of YKS on metabolic activity was low in mice and humans. Combining the above results, the P-gp inhibitory effect appears to be low in all five Kampo medicines examined in this study.…”

Basic Study of Drug-Drug Interaction between Memantine and the Traditional Japanese Kampo Medicine Yokukansan

“…In addition to this result, MEM has been demonstrated to be hardly metabolized by human CYP in studies using recombinant CYP isoforms; however, a part of it was metabolized to the gludantan form (furanose type glucuronic acid conjugate), 6-hydroxy form, and 4-hydroxy form [1]. YKS did not affect the induction and inhibition of CYPs and non-CYP enzymes [31,33,34,35]. Combined with these findings, the present results infer that plasma and brain concentrations of MEM may not be affected by co-treatment with YKS, although more detailed studies are necessary in the future.…”

“…Furthermore, cytochrome P450 (CYP) 3A4 was shown mainly to contribute to GM metabolism in human liver microsomes [30]. In a clinical study, seven-day continuous administration of YKS did not affect the activity of CYP1A2, CYP2D6, CYP3A, xanthine oxidase, or N -acetyltransferase 2 [31]. GM was also reported to be excreted in the urine [32]; however, it is not known whether the ingredients of YKS, including GM, are substrates of their transporters, and whether they induce or inhibit the transporters.…”

Influence Factors of the Pharmacokinetics of Herbal Resourced Compounds in Clinical Practice

“…Age appears to be another influence factor of pharmacokinetics, for the age-related differences in gastric emptying rate, the concentration of serum proteins, and the activity levels of drug-metabolizing enzymes, as well as the function of liver and kidney [122, 123]. Specifically, children exhibit increased CL of certain drugs, while elders show the opposite trend.…”