PHARMACOKINETICS OF KETOPROFEN ENANTIOMERS IN HEALTHY-SUBJECTS FOLLOWING SINGLE AND MULTIPLE DOSES
PHARMACOKINETICS OF KETOPROFEN ENANTIOMERS IN HEALTHY-SUBJECTS FOLLOWING SINGLE AND MULTIPLE DOSES
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DOI：
10.1002/jps.2600770113
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发表时间：
1988-01-01
影响因子：
3.8
通讯作者：
ALBALLA, SR
中科院分区：
文献类型：
--
作者：
FOSTER, RT;JAMALI, F;ALBALLA, SR
酮洛芬（KT;间苯甲酰基氢化阿托酸）是一种2-芳基丙酸（2-阿帕）非甾体抗炎药（NSAID），以外消旋混合物的形式销售和使用。虽然一般认为2-APA的活性主要是由于S-对映体，但KT药代动力学信息是基于S-和R-对映体总浓度的测量。在这项工作中，使用交叉的方式，在8名健康受试者中描述了单次（50 mg，po）和多次（50 mg，q6 h，3 d）给药后KT对映体的药代动力学。采用灵敏的立体特异性HPLC测定血浆和尿液中的KT对映体以及尿液中的结合KT对映体。单次和多次给药后计算的药代动力学指标之间无显著差异。在血浆中，发现对映异构体浓度之间存在小但显著的差异（平均S：R比为0.81 ± 0.01）。0.19在单次和0.87 . ±. 0.11重复给药后）。在尿液中发现可忽略量的原型KT对映异构体。在尿中发现超过80%的给定剂量为结合的S-和R-KT，主要的对映异构体为S-KT（平均S：R比为1.19 ± 0.01）。0.05在单个和1.17 .+-之后。0.05重复给药后）。未观察到对映异构体的消除t1/2之间存在显著差异。有人建议，立体选择性共轭，然后优先胆汁排泄的共轭R-KT对映体是负责观察到的立体选择性的药物的药代动力学。
Ketoprofen (KT; m-benzoylhydratropic acid), a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), is marketed and used as a racemic mixture. Although generally the activity of 2-APAs is suggested to be mainly due to the S-enantiomer, information on KT pharmacokinetics is based on measurement of total concentrations of S- and R-enantiomers. In this work, using a crossover fashion, the pharmacokinetics of KT enantiomers following single (50 mg, po) and then multiple (50 mg, q6h for 3 d) doses were delineated in eight healthy subjects. A sensitive stereospecific HPLC assay was used to measure KT enantiomers in plasma and urine, and conjugated KT enantiomers in urine. There were no significant differences between the pharmacokinetic indices calculated after single and multiple administration of KT. In plasma, small but significant differences were found between concentrations of the enantiomers (mean S:R ratios of 0.81 .+-. 0.19 after single and 0.87 .+-. 0.11 after repeated doses). Negligible amounts of unchanged KT enantiomers were found in urine. More than 80% of the given doses was found in urine as conjugated S- and R-KT, the predominant enantiomer being S-KT (mean S:R ratios of 1.19 .+-. 0.05 after single and 1.17 .+-. 0.05 after repeated doses). No significant difference between the elimination t1/2 of the enantiomers was observed. It is suggested that stereoselective conjugation followed by preferential biliary excretion of the conjugated R-KT enantiomer is responsible for the observed stereoselectivity in the pharmacokinetics of the drug.