Stereoselective metabolism of pentoxifylline in vitro and in vivo in humans

被引:49
|
作者
Nicklasson, M
Björkman, S
Roth, B
Jönsson, M
Höglund, P
机构
[1] Malmo Univ Hosp, Hosp Pharm, S-20502 Malmo, Sweden
[2] Lund Univ, Dept Clin Pharmacol, Lund, Sweden
关键词
stereospecific analysis; HPLC; ketone reductase; blood; erythrocytes; pharmacokinetics; humans;
D O I
10.1002/chir.10121
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Pentoxifylline increases erythrocyte flexibility, reduces blood viscosity, and inhibits platelet aggregation and is thus used in the treatment of peripheral vascular disease. It is transformed into at least seven phase I metabolites, of which two, M1 and M5, are active. The reduction of the keto group of pentoxifylline to a secondary alcohol in M1 takes place chiefly in erythrocytes, is rapidly reversible, and creates a chiral center. The aims of this study were: to develop HPLC methods to separate the enantiomers of M1, to investigate the kinetics of the reversible biotransformation of pentoxifylline to (R)- and (S)-M1 in hemolysed erythrocyte suspension, and to quantify the formation of the enantiomers of M1 (as well as M4 and M5) after intravenous and oral administration of pentoxifylline to human volunteers. (R)- and (S)-M1 could be separated preparatively on a cellobiohydrolase column, while determination in blood or plasma was by HPLC after chiral derivatization with diacetyl-L-tartaric acid anhydride. The metabolism of pentoxifylline to (R)-M1 in suspensions of hemolysed erythrocytes followed simple Michaelis-Menten kinetics (K-m = 11 mM), while that to (S)-M1 was best described by a two-enzyme model (K-m = 1.1 and 132 mM). Studies with inhibitors indicated that the enzymes were of the carbonyl reductase type. At a therapeutic blood concentration of pentoxifylline, the calculated rate of formation of (S)-M1 is 15 times higher than that of the (R)-enantiomer. Back-conversion of M1 to pentoxifylline was 3-4 times faster for the (S)- than for the (R)-enantiomer. In vivo, the R:S plasma concentration ratio of M1 ranged from 0.010-0.025 after intravenous infusion of 300 or 600 mg of pentoxifylline, and from 0.019-0.037 after oral administration of 600 mg. The biotransformation of pentoxifylline to M1 was thus highly stereoselective in favor of the (S)-enantiomer both in vitro and in vivo. (C) 2002 Wiley-Liss, Inc.
引用
收藏
页码:643 / 652
页数:10
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