期刊
PHARMACEUTICAL RESEARCH
卷 26, 期 6, 页码 1486-1495出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-009-9860-z
关键词
cannabinoid; first-pass metabolism; food effect; lymphatic transport; oral bioavailability
资金
- Novartis AG
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(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.
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