title: Chiral assay methods for lifibrol and metabolites in plasma and the observation of unidirectional chiral inversion following administration of the enantiomers to dogs.
abstract: Lifibrol, a new drug for the treatment of hypercholesterolemia, contains a stereogenic center bearing a secondary alcohol group. A normal-phase achiral-chiral HPLC separation of the enantiomers of lifibrol and two of its metabolites was developed and validated for quantitation in dog plasma. A silica and a Chiralcel OD-H column were operated in series and all six enantiomeric components and internal standard were directly separated. An initial solid-phase extraction (phenyl) clean-up step and a column-switching step to eliminate late-eluting compounds were also utilized. The solid-phase extraction step was automated using a robotic system. Assay development, validation, and application of the method to a bioavailability study of the racemate and enantiomers of lifibrol in dogs are described. The lower limit of quantitation was 0.0125 microgram/ml for each enantiomer of lifibrol using 200 microliters of dog plasma with UV detection (255 nm). In dog plasma following oral or intravenous administration of the racemate, the (R)/(S) ratio of the enantiomers of lifibrol was greater than one and increased with time. Following administration of the individual enantiomers, chiral inversion of the (S)-enantiomer but not the (R)-enantiomer was observed.
authors.affiliation: Department of Drug Metabolism Research, Upjohn Company, Kalamazoo, MI 49001.
authors.forename: R R
authors.initials: RR
authors.lastname: Walters
authors.forename: C Y
authors.initials: CY
authors.lastname: Hsu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001322:Autoanalysis; D001682:Biological Availability; D000440:Butanols / Q000097:blood* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D062385:Hydroxybenzoates / Q000097:blood* / Q000493:pharmacokinetics; D000960:Hypolipidemic Agents / Q000097:blood* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D012371:Robotics; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
chemical_list: D000440:Butanols; D062385:Hydroxybenzoates; D000960:Hypolipidemic Agents; C059343:lifibrol