National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA.
Department of Infectious Diseases, Division of Drug Discovery, Southern Research Institute, Birmingham, AL, 35205, USA.
Drug Metab Pharmacokinet. 2022 Aug;45:100463. doi: 10.1016/j.dmpk.2022.100463. Epub 2022 May 2.
Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (-)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (C) and area under the plasma concentration-time curve were higher for SPQ, while the apparent volume of distribution and total body clearance were higher for RPQ. Metabolism of the two enantiomers showed dramatic differences: plasma PQ-N-CG was derived solely from SPQ, while RPQ was much more efficiently converted to cPQ than was SPQ. C of cPQ and PQ-N-CG were 10 and 2 times higher, respectively, than the parent drugs. The study demonstrates that the PK properties of PQ enantiomers show clear differences, and metabolism is highly enantioselective. Such differences in metabolism suggest potentially distinct toxicity profiles in multi-dose regimens, especially in G6PD-deficient subjects.
伯氨喹（PQ）是一种已使用 60 年的抗疟疾药物。最近的研究表明，PQ 的两种对映异构体在动物体内的代谢方式不同，这导致了不同的药理学和毒理学特征。本研究在葡萄糖-6-磷酸脱氢酶（G6PD）活性正常的健康志愿者中，对 PQ 的单个对映异构体的药代动力学（PK）特性、代谢和耐受性进行了描述。两个队列（两个剂量水平），每个队列 18 名受试者，以交叉方式参与了三个研究臂：（-）-R 对映异构体（RPQ）的单次剂量、（+）-S 对映异构体（SPQ）的单次剂量和外消旋 PQ（RSPQ）的单次剂量。分析了 PQ 及其关键代谢物羧基伯氨喹（cPQ）和 PQ-N- 葡萄糖醛酸苷（PQ-N-CG）。观察到两种对映异构体在 PK 和代谢方面存在明显差异。与 RPQ 相比，SPQ 的 PQ 暴露量更高。SPQ 的 PQ 最大血浆浓度（C）和血浆浓度-时间曲线下面积更高，而 RPQ 的表观分布容积和总清除率更高。两种对映异构体的代谢表现出明显的差异：SPQ 可单独产生血浆 PQ-N-CG，而 RPQ 比 SPQ 更有效地转化为 cPQ。cPQ 和 PQ-N-CG 的 C 分别比母体药物高 10 倍和 2 倍。该研究表明，PQ 对映异构体的 PK 特性存在明显差异，代谢具有高度的对映选择性。这种代谢差异表明，在多剂量方案中，特别是在 G6PD 缺乏的受试者中，可能存在不同的毒性特征。
