Research Paper Intestinal Lymphatic Transport Enhances the Post-Prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-Pass Metabolism Natalie L. Trevaskis, 1 David M. Shackleford, 2 William N. Charman, 1 Glenn A. Edwards, 3 Anne Gardin, 4 Silke Appel-Dingemanse, 4 Olivier Kretz, 4 Bruno Galli, 4 and Christopher J. H. Porter 1,5 Received October 10, 2008; accepted February 18, 2009; published online March 12, 2009 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 AUC 0À1 ) 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. KEY WORDS: cannabinoid; first-pass metabolism; food effect; lymphatic transport; oral bioavailability. INTRODUCTION The most well recognised and common pathway of access to the systemic circulation following oral drug delivery is via uptake into enterocytes (intestinal absorptive cells) and transport from the intestine to the systemic circulation via the portal vein. It is becoming increasingly apparent, however, that transport into the systemic circulation via the intestinal lymphatic system may constitute an alternate, and potentially important, contributor to systemic access following oral delivery of some highly lipophilic drugs (1–5). Drug transport to the systemic circulation in association with intestinal lymph has the potential to alter drug distribution and systemic clearance (1,2,6,7) and may also impact on the extent of first- pass metabolism and oral bioavailability. Promotion of intestinal lymphatic transport has been shown to reduce first-pass metabolism within the enterocyte (by altering intracellular drug distribution patterns) (8) and by the liver (since, unlike the portal blood, the intestinal lymph empties directly into the systemic circulation without first passing through the liver) (9,10). Drug access to the intestinal lymph occurs via association with lymph lipoproteins [primarily chylomicrons (CM) and very low density lipoproteins (VLDL)] (11,12) that are assembled in the enterocyte in response to the absorption of dietary or formulation-derived lipids (13,14). As such, com- mon features of drugs that are transported via the intestinal lymph are high lipophilicity (typically log P >5 and long-chain triglyceride solubility >50 mg/g) (1,15,16) and significant increases in bioavailability after administration with the large quantities of lipid contained in food (10). However, increases in post prandial bioavailability are common for many highly lipophilic, poorly water soluble drugs since food typically enhances both lymphatic drug transport and drug solubilisa- tion in the lumen of the gastrointestinal tract (1). The 0724-8741/09/0600-1486/0 # 2009 Springer Science + Business Media, LLC 1486 Pharmaceutical Research, Vol. 26, No. 6, June 2009 ( # 2009) DOI: 10.1007/s11095-009-9860-z Studies funded by Novartis Pharma AG. 1 Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia. 2 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia. 3 Department of Veterinary Sciences, The University of Melbourne, Werribee, Victoria, Australia. 4 Novartis Pharma AG, Basel, Switzerland. 5 To whom correspondence should be addressed. (e-mail: chris. porter@pharm.monash.edu.au) ABBREVIATIONS: CM, Chylomicron; CRA, Cannabinoid receptor agonist; HDL, High density lipoprotein; LDL, Low density lipoprotein; TG, Triglyceride; VLDL, Very low density lipoprotein.