Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs.
Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs.
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DOI：
10.1093/jac/dky297
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发表时间：
2018-11-01
期刊：
影响因子：
--
通讯作者：
Tarning J
中科院分区：
文献类型：
--
作者：
Chairat K;Jittamala P;Hanboonkunupakarn B;Pukrittayakamee S;Hanpithakpong W;Blessborn D;White NJ;Day NPJ;Tarning J
外消旋伯氨喹单独给药及与常用抗疟药物联合给药后，伯氨喹和羧基伯氨喹对映体的药代动力学特性。对49名健康成年志愿者的对映体药代动力学进行了评估，这些志愿者参加了三项随机交叉研究，其中单剂量伯氨喹单独给予，然后在适当的洗脱期后与氯喹、双氢青蒿素/哌喹或吡啶/青蒿琥酯联合使用。非线性混合效应模型用于表征药代动力学并评估药物-药物相互作用的影响。与氯喹、双氢青蒿素/哌喹和吡啶/青蒿琥酯合用时，消旋型伯氨喹的分布体积中位数（95% CI）分别降低22.0%（2.24% ~ 39.9%）、24.0%（15.0% ~ 31.5%）和25.7%（20.3% ~ 31.1%）。与吡咯吡啶/青蒿琥酯合用时，伯氨喹的口服清除率中位数下降19.1%（14.5%-22.8%）。这些相互作用是对映特异性的，对(+)- s -伯氨喹的作用比(−)- r -伯氨喹的作用相对更高。两种羧基伯氨喹对映体的药代动力学均未见药物-药物相互作用。成功建立了表征伯氨喹对映体特异性的群体药代动力学模型。当与常用的抗疟疾药物共同使用时，伯氨喹的暴露量，特别是(+)- s -伯氨喹，但不包括羧基代谢物，最多增加30%。更好地了解伯氨喹的代谢机制是评估其功效和人体血液学毒性的必要条件。
Characterization of the pharmacokinetic properties of the enantiomers of primaquine and carboxyprimaquine following administration of racemic primaquine given alone and in combination with commonly used antimalarial drugs. Enantiomeric pharmacokinetics were evaluated in 49 healthy adult volunteers enrolled in three randomized cross-over studies in which a single dose of primaquine was given alone and then, after a suitable washout period, in combination with chloroquine, dihydroartemisinin/piperaquine or pyronaridine/artesunate. Non-linear mixed-effects modelling was used to characterize pharmacokinetics and assess the impact of drug–drug interactions. The volume of distribution of racemic primaquine was decreased by a median (95% CI) of 22.0% (2.24%–39.9%), 24.0% (15.0%–31.5%) and 25.7% (20.3%–31.1%) when co-administered with chloroquine, dihydroartemisinin/piperaquine and pyronaridine/artesunate, respectively. The oral clearance of primaquine was decreased by a median of 19.1% (14.5%–22.8%) when co-administered with pyronaridine/artesunate. These interactions were enantiospecific with a relatively higher effect on (+)-S-primaquine than on (−)-R-primaquine. No drug–drug interaction effects were seen on the pharmacokinetics of either carboxyprimaquine enantiomer. Population pharmacokinetic models characterizing the enantiospecific properties of primaquine were developed successfully. Exposure to primaquine, particularly to the (+)-S-primaquine but not the carboxy metabolites, increased by up to 30% when co-administered with commonly used antimalarial drugs. A better mechanistic understanding of primaquine metabolism is required for assessment of its efficacy and haematological toxicity in humans.
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影响因子：
6.1
作者：
Lindbom, L;Pihlgren, P;Jonsson, N
通讯作者：
Jonsson, N
影响因子：
3.8
作者：
Ganesan, Shobana;Tekwani, Babu L.;Walker, Larry A.
通讯作者：
Walker, Larry A.
影响因子：
4.9
作者：
Hanboonkunupakarn, Borimas;Ashley, Elizabeth A.;White, Nicholas J.
通讯作者：
White, Nicholas J.
影响因子：
3.3
作者：
LANCASTER, DL;ADIO, RA;LENNARD, MS
通讯作者：
LENNARD, MS
影响因子：
4.9
作者：
Goncalves, Bronner P.;Pett, Helmi;ter Heine, Rob
通讯作者：
ter Heine, Rob