Changes in omeprazole pharmacokinetics in rats with diabetes induced by alloxan or streptozotocin: faster clearance of omeprazole due to induction of hepatic CYP1A2 and 3A1.
OBJECTIVE
To investigate the effect of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS) on the pharmacokinetics of omeprazole in rats. It has been reported that omeprazole is primarily metabolized via hepatic CYP1A2, 2D1, and 3A1 in rats. The expression and mRNA levels of hepatic CYP1A2 and 3A1 increases in DMIA and DMIS rats, but the expression of hepatic CYP2D1 does not change in DMIS rats. In addition, the metabolic activities of intestinal CYP3A1/2 decreases in DMIS rats. Thus, it could be expected that the pharmacokinetics of omeprazole would be affected by changes in both DMIA and DMIS.


METHODS
Omeprazole was administered intravenously (20 mg/kg) and orally (40 mg/kg) to DMIA and DMIS rats and their respective controls.


RESULTS
After intravenous administration of omeprazole, the CLNR of the drug was significantly faster in DMIA (52.6 versus 67.4 mL/min/kg) and DMIS (50.2 versus 73.0 mL/min/kg) rats than the respective controls. However, after oral administration of omeprazole, the AUC was comparable between each type of diabetic rat and the respective controls.


CONCLUSIONS
The significantly faster CLNR of intravenous omeprazole could be due to increased expression and mRNA levels of hepatic CYP1A2 and 3A1 in both types of diabetic rat. The comparable AUC of oral omeprazole could be due to a decrease in the intestinal first-pass effect of omeprazole caused by decreased intestinal CYP3A1/2 in diabetic rats. Following both intravenous and oral administration in DMIA and DMIS rats, the pharmacokinetics of omeprazole were similarly altered.
Lee
Dae Young
DY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Lee
Myung G
MG
Shin
Hyun Sook
HS
Lee
Inchul
I
D000496:Alloxan; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051544:Cytochrome P-450 CYP3A; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D009853:Omeprazole / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013997:Time Factors
D013311:Streptozocin; D000496:Alloxan; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole