title: Different impacts of intestinal lymphatic transport on the oral bioavailability of structurally similar synthetic lipophilic cannabinoids: dexanabinol and PRS-211,220.
abstract: The aim of this article was to investigate the role of intestinal lymphatic transport in the oral bioavailability of two structurally similar synthetic lipophilic cannabinoids: dexanabinol and PRS-211,220. For this purpose, the long chain triglyceride (LCT) solubility and affinity to chylomicrons ex vivo of both cannabinoids were evaluated. Their oral bioavailability was assessed in rats following administration in a lipid-free and a LCT-based formulation. The intestinal lymphatic transport of these two molecules was also directly measured in a freely moving rat model. LCT solubility of dexanabinol and PRS-211,220 was 7.9+/-0.2 and 95.8+/-5.3mg/g, respectively. The uptake by chylomicrons was moderate (31.6+/-5.2%) and high (66.1+/-2.4%), respectively. The bioavailability of dexanabinol (37%) was not affected by LCT solution, whereas administration of PRS-211,220 in LCT improved the absolute oral bioavailability three-fold (from 13 to 35%) in comparison to the lipid-free formulation. The intestinal lymphatic transport of dexanabinol and PRS-211,220 was 7.5+/-0.8 and 60.7+/-6.8% of the absorbed dose, respectively. In conclusion, despite structural similarity and similar lipophilicity, dexanabinol and PRS-211,220 exhibited a very diverse pattern of oral absorption, and the lymphatic system played quite a different role in the oral bioavailability of these molecules. The low lymphatic transport of dexanabinol is likely driven by relatively lower affinity to chylomicrons and lower LCT solubility.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Pavel
authors.initials: P
authors.lastname: Gershkovich
authors.forename: Bashir
authors.initials: B
authors.lastname: Qadri
authors.forename: Avihai
authors.initials: A
authors.lastname: Yacovan
authors.forename: Shimon
authors.initials: S
authors.lastname: Amselem
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001692:Biological Transport; D002186:Cannabinoids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003314:Corn Oil / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D008208:Lymphatic System / Q000378:metabolism / Q000502:physiology*; D008297:Male; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000074241:Peanut Oil; D010938:Plant Oils / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D002186:Cannabinoids; D007093:Imidazoles; D018696:Neuroprotective Agents; C523089:PRS-211,220; D000074241:Peanut Oil; D010938:Plant Oils; D013759:Dronabinol; D003314:Corn Oil; C062018:HU 211