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.

1. 抑肝散加陈皮半夏（Yokukansankachimpihange，YKSCH）是一种结合温州蜜柑皮（Citrus unshiu peel，CUP）与半夏块茎（Pinellia tuber，PT）的汉方药方（Kampo formulation），近期被用于治疗痴呆的行为与精神症状。已有研究表明，源自CUP与PT的多种黄酮类化合物（flavonoids）具有精神药理活性，但目前尚不清楚YKSCH经口给药后，这些黄酮类化合物能否抵达脑部。
2. 本研究首先对经口给予YKSCH的大鼠的血浆与脑组织中的8种目标黄酮类化合物进行了定量检测。结果显示，血浆中可检测到橙皮苷、柚皮苷、川陈皮素与七甲氧基黄酮（heptamethoxyflavone，HMF），而脑组织中仅检测到川陈皮素与HMF。
3. 为明确CUP与PT是否会影响YKSCH中抑肝散（YKS）成分的药代动力学，本研究对经口给予YKSCH或YKS的大鼠血浆中，抑肝散代表性活性成分格西嗪甲酯（geissoschizine methyl ether，GM）的药代动力学特征进行了分析。两组大鼠的GM血浆药代动力学参数无显著差异，由此推测额外添加的两种生药不会对GM的药代动力学产生影响。
4. 综合以上结果，本研究表明，除抑肝散本身的活性成分外，源自CUP的黄酮类化合物川陈皮素与HMF可能是YKSCH发挥精神药理作用的关键物质。