A physicochemical basis for the extensive intestinal lymphatic transport of a poorly lipid soluble antimalarial, halofantrine hydrochloride, after postprandial administration to dogs
✍ Scribed by Shui-Mei Khoo; Richard J. Prankerd; Glenn A. Edwards; Christopher J.H. Porter; William N. Charman
- Book ID
- 102399859
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- English
- Weight
- 180 KB
- Volume
- 91
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
The highly lipid soluble, free-base form of halofantrine (Hf base; $ 50 mg/ mL in triglyceride lipids), a highly lipophilic (calculated log P $ 8.5) antimalarial, has recently been shown to undergo signi®cant intestinal lymphatic transport (54% of administered dose) after postprandial administration to dogs. In contrast, the clinically available hydrochloride salt of Hf (Hf Á 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 Á HCl, which was surprisingly high at 47% of the administered dose, and not signi®cantly different from that of Hf base. It was postulated that partial conversion of solubilized Hf Á 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 Á 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 Á HCl was likely to be due to the conversion of solubilized Hf Á 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.