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|Title||Intestinal Lymphatic Transport Enhances the Post-Prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-Pass Metabolism.|
|Author(s)||Trevaskis NL, Shackleford DM, Charman WN, Edwards GA, Gardin A, Appel-Dingemanse S, Kretz O, Galli B, Porter CJ.|
|Journal, Volume, Issue||Pharm Res 2009;26(6):1486-95.|
|Major outcome(s)||Systemic bioavailability of the cannabinoid CRA13 increased by more than 4-fold if taken together with a fat-rich meal.|
PURPOSE: To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. METHODS: Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. RESULTS: Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3-4.9 fold increase in [Formula: see text]) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8-20%), in spite of good absorption (72-75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. CONCLUSIONS: The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first examples of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.
|Type of publication||Medical journal|
|Address of author(s)||Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria, 3052, Australia.|