Chiang Yi-Hua, Berthold Erin C, Kuntz Michelle A, Kanumuri Siva Rama Raju, Senetra Alexandria S, Mukhopadhyay Sushobhan, Hampson Aidan J, McCurdy Christopher R, Sharma Abhisheak
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, Florida 32610, United States.
ACS Pharmacol Transl Sci. 2024 Jul 25;7(8):2452-2464. doi: 10.1021/acsptsci.4c00277. eCollection 2024 Aug 9.
This study reports the steady-state pharmacokinetic parameters for mitragynine and characterizes its elimination in male and female rats. Four male and female rats were dosed q12h with 40 mg/kg, and orally administered mitragynine for 5 and 6 days, respectively. Using a validated ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method, the plasma concentrations of mitragynine, its metabolites (7-hydroxymitragynine, 9-hydroxycorynantheidine, and mitragynine acid), and a non-CYP oxidation product (3-dehydromitragynine) were determined at various time points. Sex differences in pharmacokinetics were observed, with females demonstrating significantly higher systemic exposure of mitragynine than males. The mitragynine area under the curve normalized by the dose interval (AUC/τ) was 6741.6 ± 869.5 hng/mL in female rats and 1808.9 ± 191.3 hng/mL in males ( < 0.05). Both sexes produced similar metabolite profiles; the major metabolites were mitragynine acid and 9-hydroxycorynantheidine. 7-Hydroxymitragynine was a minor metabolite. However, higher exposure (AUCs) and the maximum plasma concentrations ( ) of active metabolites, 7-hydroxymitragynine and 9-hydroxycorynantheidine, were observed in female rats and exhibited substantial sex differences. Renal clearance of mitragynine (CL) was low (0.64 ± 0.3 mL/h in males and 0.98 ± 0.4 mL/h in females), and unchanged mitragynine accounted for <1% of the dose excreted in feces (both sexes). The clinical chemistry, complete blood count, and hematological test results reported no abnormal hematological findings after multiple dosing in either sex.
本研究报告了帽柱木碱的稳态药代动力学参数，并对其在雄性和雌性大鼠体内的消除情况进行了表征。分别对4只雄性和雌性大鼠每12小时给予40mg/kg剂量的帽柱木碱，并口服给药5天和6天。采用经过验证的超高效液相色谱-串联质谱（UPLC-MS/MS）方法，在不同时间点测定了血浆中帽柱木碱、其代谢产物（7-羟基帽柱木碱、9-羟基柯楠因碱和帽柱木酸）以及一种非CYP氧化产物（3-脱氢帽柱木碱）的浓度。观察到药代动力学存在性别差异，雌性大鼠中帽柱木碱的全身暴露量显著高于雄性。以剂量间隔标准化的帽柱木碱曲线下面积（AUC/τ）在雌性大鼠中为6741.6±869.5hng/mL，在雄性大鼠中为1808.9±191.3hng/mL（P<0.05）。两性产生的代谢产物谱相似；主要代谢产物为帽柱木酸和9-羟基柯楠因碱。7-羟基帽柱木碱是次要代谢产物。然而，在雌性大鼠中观察到活性代谢产物7-羟基帽柱木碱和9-羟基柯楠因碱的暴露量（AUCs）和最大血浆浓度（Cmax）较高，且存在显著的性别差异。帽柱木碱的肾清除率（CL）较低（雄性为0.64±0.3mL/h，雌性为0.98±0.4mL/h），粪便中排泄的未变化帽柱木碱占给药剂量的比例<1%（两性均如此）。临床化学、全血细胞计数和血液学检测结果显示，两性多次给药后均未发现异常血液学结果。
