Differentiation of Gut and Hepatic First Pass Metabolism and Secretion of Saquinavir in Ported Rabbits
| Autor: | Jeevan R. Kunta, Barbara A. Perry, Patrick J. Sinko, Helen H. Usansky |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
CYP3A Biology Pharmacology Intestinal absorption First pass effect Internal medicine medicine Animals Secretion ATP Binding Cassette Transporter Subfamily B Member 1 Saquinavir HIV Protease Inhibitors Metabolism Small intestine Bioavailability Endocrinology medicine.anatomical_structure Liver Molecular Medicine Female Rabbits Digestive System medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 310:359-366 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.103.064394 |
| Popis: | The current study was performed in intestinal and vascular access ported rabbits to quantify and differentiate the components of intestinal and hepatic first pass extraction (i.e., metabolism and secretion) of saquinavir (SQV) mediated by P-glycoprotein (P-gp) and CYP3A. SQV was administered i.v. (1–5 mg/kg) or into the upper small intestine (USI) (5 mg/kg). The roles of intestinal and hepatic secretion by means of P-gp and/or metabolism by CYP3A on the first pass gastrointestinal extraction of SQV were differentiated by using N -(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (a P-gp inhibitor), midazolam (an inhibitor of CYP3A), or cyclosporine A (an inhibitor of P-gp and CYP3A). The bioavailability (BA) of SQV after USI dosing was 4%. In the presence of CYP3A and P-gp inhibitors, the BA of SQV increased 2- to 11-fold. Based on a relatively unchanged C max but prolonged T max and t 1/2, P-gp and CYP3A inhibition appeared to alter SQV disposition (i.e., enhanced oral bioavailability by diminishing SQV elimination and by increasing its net intestinal absorption). In conclusion, the current results substantiate the role of the liver and, for the first time, experimentally establish an important role for the intestine in the net absorption and disposition of SQV. The results also demonstrate that changes in SQV disposition due to the modulation of metabolism and secretion were important and may potentially have considerable implications on multiple drug therapeutic regimens used in the treatment of AIDS. |
| Databáze: | OpenAIRE |
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