IngentaConnect Faster clearance of omeprazole in rats with acute renal failure i...

Authors: Lee, Dae Y.¹; Jung, Young S.¹; Shin, Hyun S.²; Lee, Inchul³; Kim, Young C.¹; Lee, Myung G.¹

Source: Journal of Pharmacy and Pharmacology, Volume 60, Number 7, July 2008 , pp. 843-851(9)

Abstract:

It has been reported that omeprazole is mainly metabolized via hepatic cytochrome P450 (CYP) 1A1/2, CYP2D1 and CYP3A1/2 in male Sprague-Dawley rats, and the expression of hepatic CYP3A1 is increased in male Sprague-Dawley rats with acute renal failure induced by uranyl nitrate (U-ARF rats). Thus, the metabolism of omeprazole would be expected to increase in U-ARF rats. After intravenous administration of omeprazole (20 mgkg⁻¹) to U-ARF rats, the area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly reduced (371 vs 494 μgminmL⁻¹), possibly due to the significantly faster non-renal clearance (56.6 vs 41.2 mL min⁻¹ kg⁻¹) compared with control rats. This could have been due to increased expression of hepatic CYP3A1 in U-ARF rats. After oral administration of omeprazole (40 mgkg⁻¹) to U-ARF rats, the AUC was also significantly reduced (89.3 vs 235 μg minmL⁻¹) compared with control rats. The AUC difference after oral administration (62.0% decrease) was greater than that after intravenous administration (24.9% decrease). This may have been primarily due to increased intestinal metabolism of omeprazole caused by increased expression of intestinal CYP1A and 3A subfamilies in U-ARF rats, in addition to increased hepatic metabolism.

Document Type: Research article

DOI: 10.1211/jpp.60.7.0005

Affiliations: 1: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea 2: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea; Roche Korea, Glass Tower Building, 946-1, Daechi-Dong, Gangnam-Gu, Seoul 135-706, Sou 3: Department of Diagnostic Pathology, College of Medicine, University of Ulsan, Asan Foundation, Asan Medical Center, 388-1, Poongnap 2-Dong, Songpa-Gu, Seoul 138-736, South Korea

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Faster clearance of omeprazole in rats with acute renal failure induced by uranyl nitrate: contribution of increased expression of hepatic cytochrome P450 (CYP) 3A1 and intestinal CYP1A and 3A subfamilies