Acta Pharmacologica Sinica (2009) 30: 1566–1572; doi: 10.1038/aps.2009.142; published online 12 October  2009

Aim: To quantitatively evaluate in vivo first-pass intestinal extraction of omeprazole and to investigate the possible involvement of cytochrome P450 3A 4 (CYP 3A 4) and P-glycoprotein (P-gp) in this process in rabbits.

Methods: Pharmacokinetic parameters were examined after intraduodenal (id), intraportal venous (ipv), and intravenous (iv) administration of omeprazole at various doses to intestinal and vascular access-ported rabbits.  Extraction ratios in the liver and intestinal tract were determined from the area under the plasma concentration-time curve (AUC).  In addition, omeprazole was administered by id or iv to rabbits alone or 30 min after the id administration of CYP 3A 4 or P-gp inhibitors (ketoconazole or verapamil, respectively). 

Results: Pharmacokinetic parameters of omeprazole were dose-dependent after id, ipv, and iv administration at various doses.  After id administration of 3 mg/kg omeprazole, the hepatic and intestinal extraction ratio was 57.18%±2.73% and 54.94%±1.85%, while the value was 59.29%±3.14% and 54.20%±1.53% after given 6 mg/kg, respectively.  Compared with the control group, the presence of ketoconazole (60 mg/kg) or verapamil (9 mg/kg) significantly increased the area under the plasma concentration time curve (AUC) and the peak concentration (C_max) of id-administered omeprazole, while it had no significant effect on omeprazole administered by iv. 

Conclusion: Oral omeprazole undergoes marked extraction in the small intestine, and increased bioavailability of the drug after id administration of ketoconazole and verapamil suggests that this increase results from inhibition of CYP 3A 4 and P-gp function in the intestine rather than the liver.

Keywords: omeprazole; pharmacokinetics; intestinal first-pass extraction; cytochrome P450 3A 4; P-glycoprotein; ketoconazole; verapamil