Involvement of cytochrome P450 3A4 and P-glycoprotein in first-pass intestinal extraction of omeprazole in rabbits

Abstract

Aim: To quantitatively evaluate in vivo first-pass intestinal extraction of omeprazole and to investigate the possible involvement of cytochrome P450 3A4 (CYP3A4) 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 CYP3A4 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 CYP3A4 and P-gp function in the intestine rather than the liver.

Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

“…The study found that the oral administration of OCT with P-gp/MRP2/CYP3A4 mixed inhibitors effectively decreased PVP. Previous research has demonstrated that the decreased oral bioavailability of OCT was potentially associated with the transporters P-gp and MRP2 and the metabolic enzyme CYP3A4 (16)(17)(18). The upregulated expression or activities of P-gp/MRP2/CYP3A4 further decreased OCT bioavailability in PH model rats; the present study further indicated the extended use of OCT may affect this process.…”

“…In addition, an approximately four-fold increase in absorption was observed when mixed inhibitors were administered to PH rats. Previous studies have indicated that OCT was a substrate for P-gp, MRP2 and CYP3A4 (4,(16)(17)(18). Increased expression or activities of these were observed under a PH state to decrease the intestinal absorption of OCT. To investigate the mechanism underlying the effect of the mixed inhibitors on the first pass effects, we also evaluated the expression levels of P-gp/MRP2/CYP3A4 using RT-PCR, western blot and immunohistochemistry analyses.…”

“…Certain changes of efflux transporters and metabolic enzymes have been identified in the intestine and liver in liver diseases by previous studies (18)(19)(20). Wang et al found that P-gp expression and CYP isoenzymatic activities of the small intestine were enhanced in liver fibrosis, thus inducing decreased bioavailability and increased elimination of orally administered ofloxacin (21).…”

Influence of Efavirenz and Nevirapine on the Pharmacodynamics and Pharmacokinetics of Gliclazide in Rabbits

“…Although animal models can never replace the need for comprehensive studies in human subjects, their use can provide important insights to understand and to evaluate the mechanism of potent drug interactions. It is worth noting that several fi ndings have confi rmed the functional similarity of CYP forms in rabbits and humans apart from convenience in serial blood sampling design suggesting that the rabbit is a valuable in vivo model for the assessment of drug interactions [5,19,[25][26][27][28].…”

Effect of protease inhibitors (indinavir and ritonavir) on the pharmacokinetics of gliclazide in rabbits

“…It is worth noting that several findings have confirmed the functional similarity of CYP3A forms in rabbits and humans, suggesting that the rabbit is a valuable in vivo model for the assessment of drug interaction occurring at the first pass of drugs ingested. 5,13,[17][18][19][20][21] Moreover, studies performed on rabbits, evaluating the pharmacokinetics of other drugs metabolized in humans via CYP3A4 pathway [22][23][24] have confirmed the usefulness of the rabbit model for such investigations. Based on these findings, and apart from convenience of serial blood sampling, we preferred rabbit as an animal model to perform the pharmacokinetic interaction studies.…”