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PRECLINICAL STUDY: Disposition of Δ 9 tetrahydrocannabinol in CF1 mice deficient in mdr1a P‐glycoprotein
Author(s) -
BonhommeFaivre Laurence,
Benyamina Amine,
Reynaud Michel,
Farinotti Robert,
Abbara Chadi
Publication year - 2008
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1111/j.1369-1600.2008.00096.x
Subject(s) - p glycoprotein , pharmacokinetics , bioavailability , pharmacology , chemistry , oral administration , digoxin , phenytoin , cannabinoid , medicine , biochemistry , receptor , epilepsy , psychiatry , multiple drug resistance , antibiotics , heart failure
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, Δ 9 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.