Simultaneous determination of YM928, a novel noncompetitive AMPA receptor antagonist, and its demethylated metabolite in rat, dog and monkey plasma by high-performance liquid chromatography with ultraviolet detection.
A specific HPLC method for the simultaneous determination of YM928, a novel noncompetitive AMPA receptor antagonist, and its demethylated metabolite (YM-58875) in rat, dog and monkey plasma was developed and validated. The method utilized multiple-step liquid-liquid extraction followed by a reversed-phase HPLC with UV detection at 275 nm. No interfering peaks were observed at the retention times of YM928, YM-58875 or internal standard. The validated quantitation range was 5-5000 ng/mL for both YM928 and YM-58875 when 1 mL of the plasma sample was used. The intra- and inter-day precision was less than 5.3 and 2.5% for YM928, and 3.7 and 2.3% for YM-58875, respectively. The intra- and inter-day accuracies were -8.7-5.3% and 0.7-1.9% for YM928, and -10.0-6.1% and 1.3-3.4% for YM-58875, respectively. The mean recoveries in the extraction process were 52.7-62.8%. The utility of this analytical method was demonstrated by the investigation of the pharmacokinetics of the unchanged drug and its metabolite in preclinical studies.
Kato
Kota
K
Drug Metabolism Research Laboratories, Astellas Pharma Inc., 1-8, Azusawa 1-chome, Itabashi-ku, Tokyo 174-8511, Japan. kota.kato@jp.astellas.com
Noguchi
Kiyoshi
K
Aoki
Toshiko
T
Soeishi
Yoshiaki
Y
Kamimura
Hidetaka
H
D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004285:Dogs; D004355:Drug Stability; D018691:Excitatory Amino Acid Antagonists / Q000097:blood; D000882:Haplorhini; D011725:Pyridines / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013843:Thiazines / Q000097:blood* / Q000493:pharmacokinetics
C475769:2-(N-(4-chlorophenyl)-N-methylamino)-4H-pyrido(3,2-e)-1,3-thiazin-4-one; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D018091:Receptors, AMPA; D013843:Thiazines; C517301:YM 58875