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

Postprandial administration of halofantrine (Hf), an important antimalarial , leads to 3- and 12-fold increases in oral bioavailability in humans and b eagles, 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 pr esystemic CYP3A metabolism by food components and/or recruitment of the int estinal lymphatics as an absorption pathway. Although previous rat studies confirmed Hf base is a substrate for lymphatic transport, it is difficult t o extrapolate such data to higher species, as the largely constant bile flo w in a rat precludes attainment of representative pre- and postprandial sta tes, and formulations administered to rats are often not relevant to higher species. These limitations have now been addressed by development of a con scious dog model that allows simultaneous study of intestinal lymphatic and nonlymphatic drug absorption and aspects of enterocyte-based drug metaboli sm. After oral administration of 100 mg Hf base, the mean fasted and postpr andial lymphatic transport was 1.3% and 54% of the administered dose, respe ctively. Comparison of portal and systemic plasma Hfm concentration profile s suggested enterocyte-based conversion of Hf to Hfm; however, the proporti on of Hf metabolized to Hfm was similar after fasted or postprandial admini stration. Hence, it appears that the previously observed decrease in the po stprandial metabolism of Hf is largely a consequence of significant postpra ndial intestinal lymphatic transport (which bypasses first pass hepatic met abolism). This new dog model will facilitate identification of the key fact ors that impact bioavailability, lymphatic transport, and metabolic profile s of highly lipophilic drugs. (C) 2001 Wiley-Liss, Inc. and the American Ph armaceutical Association.