LC-MS/MS detection of citrus unshiu peel-derived flavonoids in the plasma and brain after oral administration of yokukansankachimpihange in rats

1. Yokukansankachimpihange (YKSCH), a Kampo formulation combining Citrus unshiu peel (CUP) and Pinellia tuber (PT) with yokukansan (YKS), has been recently used to treat the behavioral and psychological symptoms of dementia. Several flavonoids derived from CUP and PT reportedly exhibit psychopharmacological activity, but it remains unclear whether these flavonoids reach the brain after oral administration of YKSCH. 2. In this study, we first measured eight target flavonoids in the plasma and brain in rats orally administered YKSCH. Among these flavonoids, hesperidin, narirutin, nobiletin, and heptamethoxyflavone (HMF) were detected in the plasma, and nobiletin and HMF were detected in the brain. 3. Next, to clarify whether CUP and PT affect the pharmacokinetics of YKS ingredients in YKSCH, the plasma pharmacokinetics of geissoschizine methyl ether (GM) as a representative active ingredient in YKS was examined in rats orally administered YKSCH or YKS. There was no significant difference between the two groups, inferring that the pharmacokinetics of GM may not be affected by the two additional crude drugs. 4. Taken together, this study suggests that the CUP-derived flavonoids nobiletin and HMF may be responsible for the psychopharmacological effects of YKSCH in addition to YKS ingredients.