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


CONCLUSIONS
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.
Fang
Hai-ming
HM
The Key Laboratory for Digestive Diseases of Anhui Province, Department of Gastroenterology, First Affiliated Hospital, Anhui Medical University, Hefei, China.
Xu
Jian-ming
JM
Mei
Qiao
Q
Diao
Lei
L
Chen
Mo-li
ML
Jin
Juan
J
Xu
Xin-hua
XH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000897:Anti-Ulcer Agents; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole