title: Chiral high-performance liquid chromatographic analysis of antifungal SCH 56592 and evaluation of its chiral inversion in animals and humans.
abstract: SCH 56592 is a novel triazole antifungal agent that is active both orally and intravenously in animal models of infection. This compound is in Phase II-III clinical trials for the treatment of systemic fungal infections. SCH 56592 is a single enantiomer with four stereogenic centers; therefore, it was necessary to evaluate the possible chiral inversion of this drug candidate in animals and humans. Thus, chiral high-performance liquid chromatographic (HPLC) methods have been developed to separate SCH 56592 from its diastereomers and to evaluate its chiral inversion in rats, dogs, cynomolgus monkeys, and humans. Chiral HPLC analysis involved the use of a Chiralcel OD column set at 39 degrees C with a mobile phase of hexane-ethanol-diethylamine and a fluorescence detector set at an excitation wavelength of 270 nm and an emission wavelength of 390 nm. Plasma or serum samples were subjected to solid phase extraction on a C(2) cartridge followed by HPLC analysis. The method was sensitive with a limit of quantitation of 0.1 microg/ml in dog serum. The linearity was satisfactory, as shown by correlations of >0.997 and by visual examination of the calibration curves. The precision and accuracy were satisfactory, as indicated by coefficients of variation (CV) ranging from 1.1 to 12.1% and bias values ranging from -11.0 to 9.0%. Chiral HPLC analysis indicated that SCH 56592 was not subjected to chiral inversion in rats, dogs, cynomolgus monkeys, and humans.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: C C
authors.initials: CC
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Laughlin
authors.forename: R
authors.initials: R
authors.lastname: Lovey
authors.forename: A
authors.initials: A
authors.lastname: Saksena
authors.forename: L
authors.initials: L
authors.lastname: Heimark
authors.forename: A A
authors.initials: AA
authors.lastname: Nomeir
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000032:analysis* / Q000737:chemistry* / Q000493:pharmacokinetics; D001711:Biotransformation; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D015203:Reproducibility of Results; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism; D014230:Triazoles / Q000032:analysis* / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole