Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism.
OBJECTIVE
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 AUC(0 - infinity)) 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.
Trevaskis
Natalie L
NL
Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
Shackleford
David M
DM
Charman
William N
WN
Edwards
Glenn A
GA
Gardin
Anne
A
Appel-Dingemanse
Silke
S
Kretz
Olivier
O
Galli
Bruno
B
Porter
Christopher J H
CJ
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D063386:Cannabinoid Receptor Agonists; D004285:Dogs; D005215:Fasting; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology*; D019518:Postprandial Period; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
D063386:Cannabinoid Receptor Agonists; D009281:Naphthalenes; D014280:Triglycerides; C541946:cannabinoid receptor agonist 13