Different impacts of intestinal lymphatic transport on the oral bioavailability of structurally similar synthetic lipophilic cannabinoids: Dexanabinol and PRS-211,220

• Published in: European journal of pharmaceutical sciences Vol. 31; no. 5; pp. 298 - 305
• Main Authors: Gershkovich, Pavel, Qadri, Bashir, Yacovan, Avihai, Amselem, Shimon, Hoffman, Amnon
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01.08.2007; Elsevier
• Subjects: Administration, Oral; Animals; Area Under Curve; Bioavailability; Biological and medical sciences; Biological Availability; Biological Transport; Cannabinoids; Cannabinoids - administration & dosage; Cannabinoids - chemistry; Cannabinoids - pharmacokinetics; Chylomicrons; Corn Oil - chemistry; Dose-Response Relationship, Drug; Dronabinol - administration & dosage; Dronabinol - analogs & derivatives; Dronabinol - chemistry; Dronabinol - pharmacokinetics; General pharmacology; Half-Life; Imidazoles - administration & dosage; Imidazoles - pharmacokinetics; Injections, Intravenous; Intestines - metabolism; Lipophilicity; Lymphatic System - metabolism; Lymphatic System - physiology; Lymphatic transport; Male; Medical sciences; Molecular Structure; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacokinetics; Peanut Oil; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Plant Oils - chemistry; Rats; Rats, Wistar; Structure-Activity Relationship; clog P; Chylomicrons; CM; Bioavailability; TFA; Cannabinoids; TG; THF; DDW; Lymphatic transport; NMDA; LCT; Lipophilicity; Lymphatic system; Pharmaceutical technology; Biological transport; Gut; Oral administration; Lymphatic; Cannabinoid; Pharmacokinetics
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2007.04.006

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 ± 5.3 mg/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.