A conscious dog model for assessing the absorption, enterocyte-based metabolism, and intestinal lymphatic transport of halofantrine

✍ Scribed by Shui-Mei Khoo; Glenn A. Edwards; Christopher J.H. Porter; William N. Charman

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 161 KB
• Volume: 90
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.1110

✦ Synopsis

Postprandial administration of halofantrine (Hf), an important antimalarial, leads to 3-and 12-fold increases in oral bioavailability in humans and beagles, respectively, and corresponding 2.4-fold and 6.8-fold decreases in metabolic conversion to desbutylhalofantrine (Hfm). Factors contributing to the decreased postprandial metabolism of Hf could include inhibition of presystemic CYP3A metabolism by food components and/or recruitment of the intestinal lymphatics as an absorption pathway. Although previous rat studies con®rmed Hf base is a substrate for lymphatic transport, it is dif®cult to extrapolate such data to higher species, as the largely constant bile ¯ow in a rat precludes attainment of representative pre-and postprandial states, and formulations administered to rats are often not relevant to higher species. These limitations have now been addressed by development of a conscious dog model that allows simultaneous study of intestinal lymphatic and nonlymphatic drug absorption and aspects of enterocyte-based drug metabolism. After oral administration of 100 mg Hf base, the mean fasted and postprandial lymphatic transport was 1.3% and 54% of the administered dose, respectively. Comparison of portal and systemic plasma Hfm concentration pro®les suggested enterocyte-based conversion of Hf to Hfm; however, the proportion of Hf metabolized to Hfm was similar after fasted or postprandial administration. Hence, it appears that the previously observed decrease in the postprandial metabolism of Hf is largely a consequence of signi®cant postprandial intestinal lymphatic transport (which bypasses ®rst pass hepatic metabolism). This new dog model will facilitate identi®cation of the key factors that impact bioavailability, lymphatic transport, and metabolic pro®les of highly lipophilic drugs.