Effect of bile on the oral absorption of halofantrine in polyethylene glycol 400 and polysorbate 80 formulations dosed to bile duct cannulated rats.

Objectives: The aim of this study was to examine the effects of bile on the oral absorption of the poorly water-soluble compound, halofantrine, when administered to rats in vehicles consisting of the co-solvent polyethylene glycol 400 (PEG 400) alone or in mixtures with the surfactant polysorbate 80 (PS 80) (95:5; 85:15; 75:25 PEG 400:PS 80).

Methods: Halofantrine (17.5 mg/kg) was administered to bile duct cannulated (BDC) and sham-operated rats in a fixed vehicle volume of 5 ml/kg.

Key Findings: The bioavailability of halofantrine was significantly lower in BDC rats when dosed with 0-5% PS 80 in PEG 400 compared with BDC rats dosed with >15% PS 80. Increasing the concentration of PS 80 to 15-100% eliminated this difference. A possible explanation for the lower bioavailability of halofantrine in BDC rats when dosed in pure PEG 400 could be the dilution of the vehicle by intestinal fluids, decreased transit time and precipitation in the gastrointestinal tract upon dilution of PEG 400.

Conclusions: The addition of PS 80 to the formulation increased its solubilising power upon dilution and may have inhibited precipitation and substituted the absence of bile above a certain level. Adjusting the level of surfactant in drug formulations could therefore be used to minimise variability in the bioavailability from co-solvent systems based upon differences in bile concentration between individuals.