A physicochemical basis for the extensive intestinal lymphatic transport of a poorly lipid soluble antimalarial, halofantrine hydrochloride, after postprandial administration to dogs.

The highly lipid soluble, free-base form of halofantrine (Hf base; approximately 50 mg/mL in triglyceride lipids), a highly lipophilic (calculated log P approximately 8.5) antimalarial, has recently been shown to undergo significant intestinal lymphatic transport (54% of administered dose) after postprandial administration to dogs. In contrast, the clinically available hydrochloride salt of Hf (Hf small middle dot HCl), was not considered to be a likely substrate for lymphatic transport because its solubility in long-chain triglyceride lipids is low (< 1 mg/mL). This paper reports the lymphatic transport of Hf after postprandial administration of Hf.HCl, which was surprisingly high at 47% of the administered dose, and not significantly different from that of Hf base. It was postulated that partial conversion of solubilized Hf.HCl to the highly lipid soluble Hf base within the intestinal lumen might account for the extensive lymphatic transport. However, as Hf is a tertiary amine with an expected pK(a) of > 10, at gastrointestinal pH, the fraction of Hf present as the free base form is likely to be extremely low. Physicochemical studies exploring the solubility and pK(a) of Hf suggest that Hf.HCl was extensively solubilized following fed administration. When solubilized in representative fed state mixed micellar solutions, its apparent pK(a) was 6.92 and considerably lower than anticipated for a tertiary amine. It appears that the extensive lymphatic transport of Hf observed after postprandial administration of Hf.HCl was likely to be due to the conversion of solubilized Hf.HCl to the free base. Therefore, in addition to indicators such as log P and triglyceride solubility, factors such as drug solubilization in representative fed state intestinal conditions and the possible conversion to the un-ionized form should be considered when predicting the potential lymphatic transport of salts of poorly water soluble acids and bases.

Khoo SM ，Prankerd RJ ，Edwards GA ，Porter CJ ，Charman WN ... -  《JOURNAL OF PHARMACEUTICAL SCIENCES》

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 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 confirmed Hf base is a substrate for lymphatic transport, it is difficult to extrapolate such data to higher species, as the largely constant bile flow 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 profiles 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 significant postprandial intestinal lymphatic transport (which bypasses first pass hepatic metabolism). This new dog model will facilitate identification of the key factors that impact bioavailability, lymphatic transport, and metabolic profiles of highly lipophilic drugs.

Khoo SM ，Edwards GA ，Porter CJ ，Charman WN ... -  《JOURNAL OF PHARMACEUTICAL SCIENCES》

A physicochemical basis for the effect of food on the absolute oral bioavailability of halofantrine.

Humberstone AJ ，Porter CJ ，Charman WN 《-》

Partitioning of halofantrine hydrochloride between water, micellar solutions, and soybean oil: Effects on its apparent ionization constant.

Recent studies in a conscious dog model demonstrated intestinal lymphatic transport to be a significant contributor to the bioavailability of the highly lipid-soluble free-base of halofantrine (Hf), and surprisingly, also the poorly lipid-soluble hydrochloride salt (Hf. HCl). Partial conversion of solubilized Hf. HCl to Hf base within the intestinal lumen prior to the lymphatic uptake seemed to be the most likely explanation for these results. This hypothesis was supported by studies exploring the partitioning behavior of Hf. HCl between soybean oil (SBO) and aqueous micellar solutions containing different ionic and nonionic surfactants. Mixed micelles prepared from sodium taurodeoxycholate (NaTC) and lecithin (PC) were chosen to represent fed-state intestinal fluids. The apparent ionization constants derived from the partitioning versus pH profiles showed marked shifts when compared with the likely aqueous pK(a) value. In the present paper, the apparent pK(a) values of Hf in aqueous micellar phases, without a coexisting oil phase, were investigated to further probe the mechanisms underlying the effect of micellar media on the apparent ionization equilibrium, and subsequently, on its partitioning behavior in the triphasic systems. Another aim of this study was to further evaluate the aqueous pK(a) value of Hf. The results indicate that the aqueous pK(a) of Hf is most probably in the range approximately 8-9, and that the ionization equilibrium is highly dependent on the solution environment. For example, marked pK(a) shifts of several units were observed for Hf in the presence of different micellar species and SBO. The apparent ionization equilibrium depends not only on interaction of Hf with the micelles, but also on its partitioning into the oil phase.

Taillardat-Bertschinger A ，Perry CS ，Galland A ，Prankerd RJ ，Charman WN ... -  《-》

Lymphatic transport of halofantrine in the conscious rat when administered as either the free base or the hydrochloride salt: effect of lipid class and lipid vehicle dispersion.

Porter CJ ，Charman SA ，Humberstone AJ ，Charman WN ... -  《JOURNAL OF PHARMACEUTICAL SCIENCES》