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.
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 microg min mL(-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 microg min mL(-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.
Lee
Dae Y
DY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Jung
Young S
YS
Shin
Hyun S
HS
Lee
Inchul
I
Kim
Young C
YC
Lee
Myung G
MG
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology*; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology*; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D003580:Cytochromes; D007422:Intestines / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008657:Metabolic Clearance Rate; D009853:Omeprazole / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014502:Uranyl Nitrate
D003580:Cytochromes; D014502:Uranyl Nitrate; D019392:Cytochrome P-450 CYP2E1; C017170:Cyp1a2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole