Disposition of Delta tetrahydrocannabinol in CF1 mice deficient in mdr1a P-glycoprotein.
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, Delta(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 microg/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.
Bonhomme-Faivre
Laurence
L
Department of Pharmacology and Pharmacy, Hôpital Paul Brousse, 14 Avenue Paul Vaillant Couturier, 94800 Villejuif, France. laurence.bonhomme-faivre@pbr.aphp.fr
Benyamina
Amine
A
Reynaud
Michel
M
Farinotti
Robert
R
Abbara
Chadi
C
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D025222:Chloroplast Proton-Translocating ATPases / Q000378:metabolism*; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics; D013759:Dronabinol / Q000097:blood / Q000493:pharmacokinetics*; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D006213:Hallucinogens / Q000097:blood / Q000493:pharmacokinetics*; D007267:Injections; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D011509:Proteoglycans / Q000378:metabolism*; D013997:Time Factors
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D006213:Hallucinogens; D011509:Proteoglycans; D004077:Digoxin; D013759:Dronabinol; C095122:multidrug resistance protein 3; D025222:Chloroplast Proton-Translocating ATPases