Prediction of in vivo enantiomeric compositions by modeling in vitro metabolic profiles.
Identification and quantitation of drug metabolites are important for understanding and predicting drug-drug interactions and toxicities. For chiral compounds, metabolic interconversion of enantiomers may present unique challenges. If the stereoisomers are biologically distinguishable, regulatory agencies consider them distinct chemical entities and require individual characterization since enantiomers may exhibit different pharmacokinetic, pharmacologic, and toxicologic properties. Efforts to predict enantiomeric ratios in humans from animal studies are frequently hampered by a lack of understanding of the enzymes responsible and potential interspecies differences. In this study, liver microsomes from rats, dogs, and monkeys were used to investigate the kinetics of interconversion of two enantiomeric secondary alcohols (Compounds A and C) via oxidation to a ketone intermediate (Compound B) and subsequent reduction of the ketone to either regenerate the starting alcohol, or produce the enantiomer. A mechanistic model was established using in vitro microsomal data to predict the ratios of the enantiomer concentrations in plasma 24 hours after dosing and the ratios of AUC values for the enantiomers. Plasma concentrations of the enantiomers and ketone intermediate were determined after single intravenous and oral doses of Compound C. The observed concentration and AUC ratios were similar to the values predicted by the mechanistic model.
Wang
Mengmeng
M
Pf.Zcf, Andover, MA 01810, USA.
Wang
Qi
Q
Cai
Hong
H
Sleczka
Bogdan
B
D'Arienzo
Celia
C
Josephs
Jonathan
J
Ye
Xiang-Yang
XY
Robl
Jeffrey
J
Gordon
David
D
Rodrigues
David
D
Harper
Timothy
T
D000438:Alcohols / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D004285:Dogs; D000882:Haplorhini; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000438:Alcohols; D004364:Pharmaceutical Preparations