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

Abstract

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.

Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug–bile interaction

“…Figure 2 shows the recovery profile of YM466 following the ultrafiltration of YM466 mixed with various amount of bile. The recovery of YM466 was significantly decreased by the addition of bile in a dose‐dependent manner and reached as low as 30% in the presence of 5 mg/mL of bile, which almost corresponds to the bile concentration in the upper gastrointestinal tract in humans, 2–8 mg/mL as sodium taurocholate 5,8–10. This result indicates that YM466 interacts with bile to form a large complex with poor solubility, confirming our previous report that the solubility of YM466 was extensively decreased in the presence of bile and that the absorption of YM466 in the presence of bile was decreased to almost 35% in a rat intestinal administration study 5.…”

“…Sodium taurocholate was used at 8 mM (ca. 4.3 mg/mL) as a representative bile salt, as it has often been used as a component of simulated human intestinal fluids8,12 and it has been reported that the bile salt concentrations in the upper gastrointestinal tract in human ranged from 3 to 15 mM 5,8–10. As shown in Figure 5A, the recovery of YM466 into the filtrate was not affected by AAM copolymer E at all.…”

“…Bile is constantly secreted in rats and the level of bile salt in rat jejunum is reported to be about 9–17 mM, corresponding to 4.8–9.1 mg/mL as sodium taurocholate 10. On the basis of the levels of bile salt in rats, the P–B ratio after oral dosing of the formulations of P–D ratio 1 and 3 (Fig.…”

Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

“…Similar observations were made in a different study, where the effects of bile on the oral absorption of halofantrine administered to rats in vehicles consisting of the cosolvent polyethylene glycol 400 alone or in mixtures with the surfactant polysorbate 80 were studied. 32 It was suggested that the addition of exogenous surfactants above a certain concentration threshold rendered the bioavailability of the formulation more bile composition independent. So far, excipient selection still remains highly empirical, and extensive screenings are often required to obtain drug-excipient combinations that optimize formulation stability.…”

Techniques of Experimentation

“…In larger species, such as the dog, pig, and nonhuman primate, bile can be aspirated by cholecystocentesis under ultrasound guidance (Neel et al, 2006;Pekow et al, 1994). Cannulation of the common bile duct is described by several authors in a variety of species including the rat (Tønsberg et al, 2011), mouse (Manautou and Chen, 2005), rabbit (West et al, 2002), guinea pig (Yu and Shen, 1991), pig (Faidley et al, 1991), and dog (Kissinger et al, 1998;Barringer et al, 1982;Soli and Birkeland, 1977;Knapp et al, 1971). Surgically modified, chronically catheterized mice, rats, and other species are commonly available from laboratory animal vendors.…”