Pharmacokinetics-based elucidation on disparity in clinical effectiveness between varieties of Zhi Zhu Wan, a Traditional Chinese Medical formula

Aim: Zhi Zhu Wan (ZZW) is a classical Chinese medical formulation used for the treatment of functional dyspepsia that attributed to Spleen-deficiency Syndrome. ZZW contains Atractylodes Rhizome and Fructus Citrus Immaturus, the later originates from both Citrus aurantium L. (BZZW) and Citrus sinensis Osbeck (RZZW). The present study is designed to elucidate disparities in the clinical efficacy of two ZZW varieties based on the pharmacokinetics of naringenin and hesperetin. Mehtod: After oral administration of ZZWs, blood sample was collected from healthy volunteers at designed time points. Naringenin and hesperetin were detected in plasma by RP-HPLC, pharmacokinetic parameters were processed using mode-independent methods with WINNONLIN. Results: After oral administration of BZZW, both naringenin and hesperetin were detected in plasma, and demonstrated similar pharmacokinetic parameters. Ka was 0.384±0.165 and 0.401±0.159, T_1/2(ke)(h) was 5.491±3.926 and 5.824±3.067, the AUC (mg/Lh) was 34.886±22.199 and 39.407±19.535 for naringenin and hesperetin, respectively. However, in the case of RZZW, only hesperetin was found in plasma, but the pharmacokinetic properties for hesperetin in RZZW was different from that in BZZW. T_max for hesperetin in RZZW is about 8.515h, and its C_max is much larger than that of BZZW. Moreover, it was eliminated slowly as it possessed a much larger AUC value. Conclusion: The distinct therapeutic orientations of the Chinese medical formula ZZWs with different Fructus Citrus Immaturus could be elucidated based on the pharmacokinetic parameters of constituents after oral administration.