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Disposition of Δ9 tetrahydrocannabinol in CF1 mice deficient in mdr1a P-glycoprotein

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Abstract:

ABSTRACT

P-glycoprotein (P-gp) plays a major role in drug efflux. All the transported substrates are more or less hydrophobic and amphiphatic in nature. Being lipophilic, Δ9 tetrahydrocannabinol (THC), the main cannabis component, could be a potential P-gp substrate. The aim of this project was to determine the contribution of the mdr1a gene product to THC disposition. Therefore, oral THC and digoxin (substrate test for P-gp) pharmacokinetics have been investigated in the intestinal epithelium and in the brain capillary endothelium of CF1 mdr1a (−/−) mice (mice naturally deficient in P-gp). These pharmacokinetics were compared to THC and digoxin oral pharmacokinetics in wild type mice mdr1a (+/+) (not P-gp deficient). The application of Bailer's method showed that THC total exposure measured by the area under the plasma concentration time curve was 2.17-fold higher in CF1 mice naturally deficient in P-gp than in wild type mice after oral administration of 25 mg/kg of THC, and 2.4-fold higher after oral administration of 33 µg/kg of digoxin. As a consequence, the oral bioavailability of THC and digoxin was higher in naturally P-gp-deficient mice. We concluded that P-gp limits THC oral uptake and mediates direct drug excretion from the systemic circulation into the intestinal lumen.

Keywords: CF1 mice; P-glycoprotein; THC; digoxin; multidrug resistance; Δ9 tetrahydrocannabinol

Document Type: Research Article

DOI: http://dx.doi.org/10.1111/j.1369-1600.2008.00096.x

Affiliations: 1: Department of Psychiatry and Addictology, 2: Assistance Publique Hôpitaux de Paris (APHP), Hôpital Paul Brousse, France and Clinical Pharmacy Department (UPRES 2706) University Paris XI, Faculty of Pharmacy, France 3: Department of Pharmacology and Pharmacy and

Publication date: September 1, 2008

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