Real-time monitoring of metabolic reactions by microdialysis in combination with tandem mass spectrometry: hydrolysis of CS-866 in vitro in human and rat plasma, livers, and small intestines.
Microdialysis combined with tandem mass spectrometry was used to monitor the rapid hydrolysis of CS-866, a new prodrug-type angiotensin II receptor antagonist, in vitro in rat and human plasma as well as in hepatic and intestinal preparations. No chromatographic separation was conducted, and the ion intensity of CS-866 in MS/MS was directly used to perform data acquisition at intervals not longer than several seconds. A methanol-dialyzing medium, flow rate of dialysate, and adoption of sheath liquid were contrived to facilitate this method of measurement. The use of the methanol-dialyzing medium resulted in the effective extraction of the lipophilic analyte through the dialyzing membrane and a substantial reduction of inorganic substances introduced into the ion source. The calibration curve for CS-866 was linear over a concentration range from 0.2 to 20 microM (R(2) = 0.9998), and the intraassay precision was at an acceptable level of not more than 15% in coefficient of variation percentage. CS-866 was hydrolyzed very rapidly to RNH-6270, the pharmacologically active metabolite, in rat and human plasma and rat liver microsomes, and the hydrolysis proceeded extremely rapidly in human plasma with a half-life of less than several seconds.
Kobayashi
N
N
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Tokyo, Shinagawa-ku, 140-8710, Japan.
Fujimori
I
I
Watanabe
M
M
Ikeda
T
T
D000818:Animals; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006868:Hydrolysis; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics*; D007421:Intestine, Small / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D017551:Microdialysis / Q000379:methods*; D000068557:Olmesartan Medoxomil; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics*
D007093:Imidazoles; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil