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

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). 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. 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. 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.

Tønsberg H ，Holm R ，Mu H ，Boll JB ，Jacobsen J ，Müllertz A ... -  《-》

Effects of polysorbate 80 on the in-vitro precipitation and oral bioavailability of halofantrine from polyethylene glycol 400 formulations in rats.

Tønsberg H ，Holm R ，Bisgaard J ，Jacobsen J ，Müllertz A ... -  《-》

Intestinal lymphatic transport of halofantrine in rats assessed using a chylomicron flow blocking approach: the influence of polysorbate 60 and 80.

Lind ML ，Jacobsen J ，Holm R ，Müllertz A ... -  《EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES》

Using resin to generate a non-invasive intestinal bile-depleted rat model was unsuccessful.

The purpose of this study was to evaluate if a rat model, based upon co-administration of the anion-exchanging resin, cholestyramine, could replace surgery when evaluating the importance of bile on drug absorption. Two different formulations were used for the administration of halofantrine; polyethylene glycol 400 (PEG 400) and PEG 400/polysorbate 80 (50:50, w/w%), as a positive and negative control on the dependency of bile. No significant effect of the resin was detected after evaluation of three different pre-dosing regimes, but in line with previous studies the formulation containing polysorbate 80 showed a significant increase in the absorption of halofantrine. This study therefore demonstrates that the pre-dosing of rats with Cholestyramine can not replace surgical bile duct cannulation if a formulation needs to be evaluated for its bile dependency.

Holm R ，Hesselkilde JZ ，Jørgensen EB ，Müllertz A ... -  《-》

Influence of bile on the absorption of halofantrine from lipid-based formulations.

The bioavailability of the poorly soluble model drug halofantrine, dosed in a soy bean oil solution or in a self-nanoemulsifying drug delivery system (SNEDDS), at two levels of lipid, was assessed in rats. Three rat models were used: intact rats, sham-operated rats and bile duct cannulated rats. The study showed no difference in the pharmacokinetic parameters between intact and sham-operated rats. T(max) increased with lipid load for both oil solution and SNEDDS, whereas C(max) and the absolute bioavailability were significantly higher for the SNEDDS at both lipid dosing levels. Bile duct cannulation of the rats reduced the C(max) and the absolute bioavailability of halofantrine significantly, by a factor of 2, for all 4 treatments. These data clearly demonstrate that bile has an importance for the absorption of drugs from lipid-based formulations independent of the type.

Holm R ，Tønsberg H ，Jørgensen EB ，Abedinpour P ，Farsad S ，Müllertz A ... -  《-》