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

Olmesartan Medoxomil, an Angiotensin II Receptor Blocker Ameliorates Insulin Resistance and Decreases Triglyceride Production in Fructose-Fed Rats

“…The doses of olmesartan administrated were comparable between the chow-fed and fructose-fed animals ( Table 1). The plasma concentration of olmesartan after ingestion of 0.5 mg/kg olmesartan was measured in 3 rats; the maximum plasma concentration was 75.4 0.4 ng/ml, which fell within the safe range (the toxic dose is above 100 mg/kg for male rats) (8). SBP was significantly higher in fructose-fed rats than in chow-fed rats (138 11 vs. 126 7 mmHg; p<0.05).…”

“…On the day of the experiment, food was removed at 9:00 AM but the drinking water remained available, and the experiment was started at 2:00 PM (5 h-fasting state). In three rats, we measured the plasma concentration of olmesartan by high performance liquid chromatography (HPLC) (8) at the very start of the experiments. All procedures were performed in accordance with the "Guide for the Care and Use of Laboratory Animals" of Showa University, and were approved by the Animal Care and Use Committee of that institution.…”

Paraoxonase 1 as a Major Bioactivating Hydrolase for Olmesartan Medoxomil in Human Blood Circulation: Molecular Identification and Contribution to Plasma Metabolism

“…However, the plasma esterase PON1, presumably in the portal blood, may play a supplemental role to complete the bioactivation of prodrug molecules that escape hydrolysis by CMBL in the intestine. Although the transit time through portal blood is quite short, the possibility of a significant contribution of plasma PON1 was indicated in our previous publication (Kobayashi et al, 2000), which showed that OM hydrolysis proceeds in human plasma with a half-life of less than several seconds. This multiple-enzyme contribution at multiple sites is considered to effectuate the minimal risk of significant interindividual variation regardless of possible inhibition by concomitantly administered drugs or genetic polymorphisms in CMBL that may cause varied production of the pharmacologically active metabolite.…”

Quantitative determination of olmesartan in human plasma and urine by liquid chromatography coupled to tandem mass spectrometry

“…The drug contains a medoxomil ester moiety and is cleaved rapidly by an endogenous esterase to release the active metabolite olmesartan [2]. Due to the fact that hydrolysis of olmesartan medoxomil in human plasma is extremely rapid [3], determination of olmesartan in plasma is the only choice for the study of pharmacokinetic profile of olmesartan medoxomil. Up to date, olmesartan has been determined in plasma and other biological fluids using high performance liquid chromatography (HPLC) coupled to fluorescent detection [4,5].…”