High-performance liquid chromatographic analysis of the anti-tumor agent SCH 66336 in cynomolgus monkey plasma and evaluation of its chiral inversion in animals.
SCH 66336 is a novel non-cytotoxic anti-tumor agent that is in phase I/II clinical trials for the treatment of solid tumors. This compound is a single enantiomer with one chiral center. Prior to evaluation of this drug candidate in man, it was necessary to evaluate its pharmacokinetics and possible chiral inversion in animals. Thus, high-performance liquid chromatographic (HPLC) methods have been developed for its determination in cynomolgus monkey plasma and for the evaluation of its chiral inversion in rats and cynomolgus monkeys. The achiral HPLC analysis involved extraction with 30% methylene chloride in hexane followed by separation on a CN column and quantitation by UV absorbance at 280 nm. The method was linear over a concentration range of 0.1 to 20 microg/ml in monkey plasma. The chiral HPLC analysis involved the use of a Chiralpak AD column set at 39 degrees C with a mobile phase of hexane-ethanol-diethylamine mixture and a UV detector set at 280 nm. Plasma samples were subjected to solid-phase extraction on a C2 cartridge prior to HPLC analysis. The method was linear over a concentration range of 0.25 to 10 microg/ml in rat and cynomolgus monkey plasma for both enantiomers. Both methods showed good linearity (r2>0.99), accuracy (bias< 13%) and precision (CV<12%). Chiral HPLC analysis indicated that SCH 66336 was not subjected to chiral inversion in rats and cynomolgus monkeys.
Kim
H
H
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Likhari
P
P
Lin
C C
CC
Nomeir
A A
AA
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D008252:Macaca fascicularis; D008297:Male; D010880:Piperidines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D011725:Pyridines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D003986:Dibenzocycloheptenes
D000970:Antineoplastic Agents; D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes