Does stereoselective lymphatic absorption contribute to the enantioselective pharmacokinetics of halofantrine In Vivo?

Abstract

Halofantrine (Hf) is a chiral, lipophilic phenanthrene methanol antimalarial which exhibits both enantioselective plasma pharmacokinetics and extensive lymphatic absorption when administered postprandially. In order to determine whether enantioselective lymphatic absorption contributes to the previously reported enantioselective pharmacokinetics of Hf, lymph samples collected from thoracic duct-cannulated dogs dosed with racemic Hf (100 mg, administered postprandially) were assayed with a chiral HPLC method capable of quantifying the relative amounts of (+)- and (-)-Hf. During the period when the majority (>95%) of Hf transport into lymph occurred (0-5 h post dose), essentially equal amounts of the two enantiomers were present in the intestinal lymph. At later times (e.g. 5-12 h post dose), there was a steady increase in the fraction of (+)-Hf present in lymph. The trends evident at later time points most likely reflect an increase in the proportion of (+)-Hf present in systemic blood, (resulting from enantioselective systemic metabolism) and a corresponding increase in (+)-Hf in the thoracic lymph by equilibration of drug across blood and lymphatic capillaries, as opposed to enantioselective lymphatic transport per se. This study was the first to examine the possibility of stereoselectivity in lymphatic transport, however, the data suggest that drug absorption (at least in the case of halofantrine) via the intestinal lymphatics is not enantioselective.

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

“…For highly lipophilic compounds, drug often enters the systemic circulation via lymphatic transport. The lymphatic absorption of halofantrine enantiomers has been examined [20], and was found to be initially nonstereoselective after oral administration of racemic halofantrine to intestinal lymphatic-cannulated dogs. Interestingly, with the progression of time stereoselectivity began to appear in the lymph concentrations of halofantrine enantiomers, with concentrations of ðþÞ enantiomer exceeding those of antipode.…”