Stereospecific pharmacokinetic characterisation of phenprocoumon metabolites, and mass-spectrometric identification of two novel metabolites in human plasma and liver microsomes

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• 作者：Bernd Kammerer ; Rainer Kahlich ; Mike Ufer ; Andreas Schenkel ; Stefan Laufer and Christoph H. Gleiter
• 关键词：Phenprocoumon metabolism ; Chiral discrimination effects ; LC– ; MS coupling
• 刊名：Analytical and Bioanalytical Chemistry
• 出版年：2005
• 出版时间：November 2005
• 年：2005
• 卷：383
• 期：6
• 页码：909-917
• 全文大小：254 KB
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Analytical Chemistry
  Food Science
  Inorganic Chemistry
  Physical Chemistry
  Monitoring, Environmental Analysis and Environmental Ecotoxicology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1618-2650

文摘

Phenprocoumon belongs to the group of vitamin K antagonists (VKAs), for example warfarin and acenocoumarol. It is widely used for therapeutic anticoagulation and clinically administered as a racemate. Both enantiomers are partially metabolized by the polymorphic CYP2C9 enzyme. The pharmacokinetics are, however, substantially less dependent on CYP2C9 activity or genotype than for other CYP2C9-metabolised VKAs, and pharmacokinetic differences for the enantiomers are only minor. We have investigated the stereospecific pharmacokinetics of the monohydroxylated phenprocoumon metabolites in human plasma by achiral–chiral LC–LC–MS–MS coupling. In addition to the known metabolites, 4′-, 6-, and 7-hydroxyphenprocoumon, two other monohydroxylated metabolites (M1 and M2) were detected in plasma and human liver microsomal incubations. One of these was identified as 2′-hydroxyphenprocoumon by comparison with synthetic standards; the other seemed to be a side-chain-hydroxylated derivative. Analysis of enantiomeric metabolite ratios after a single oral dose of phenprocoumon revealed changes over time with an overall preponderance of the respective (R) enantiomers. The minor role of CYP2C9 in 4′-hydroxy-PPC formation and the effect of CYP2C9 genotype for (S)-6- and (S)-7-hydroxy-PPC were confirmed. M1 and M2 are formed highly stereoselectively, without dependence on CYP2C9 genotype. These may be interpreted as alternative metabolic pathways that render phenprocoumon less dependent on CYP2C9 activity or genotype.