Grapefruit juice also diminished the AUC of fexofenadine variably among
individuals. This decreased oral bioavailability is likely a contribution of direct
inhibition of its uptake by intestinal OATP-A (Dresser et al., 2005).
6.5.5 Formulation Effect
Formulation strategies to overcome multidrug resistance have been evaluated
for their enhancement of membrane permeability of a drug and inhibition of
P-gp. Surfactants used in pharmaceutical formulations include nonionic
detergents, polyoxyethylen(20)-sorbitanemonooleate (Tween 80), polyoxyethylen–
polyoxypropylene block copolymers (e.g., Pluronic P85), and polyoxyethy-
lenglycoltriticinoleate (Cremophor EL). These agents can modulate drug
absorption by multiple mechanisms including inhibition of intestinal P-gp.
Water-soluble vitamin E (D-alpha-tocopheryl poly(ethylene glycol) 1000
succinate (TPGS 1000), which is comprised of a hydrophilic polar head and
a lipophilic alkyl tail, has been used as a solubilizer, an emulsifier, and an
effective oral absorption enhancer.
In murine monocytic leukemia cells overexpressing P-gp, P-gp-mediated
rhodamine123 transport was inhibited by five nonionic surfactants in a
concentration-dependent manner and in the order TPGS>Pluronic
PE8100>Cremophor EL>Pluronic PE6100 Tween 80. In contrast,
none of those surfactants showed a significant inhibition of MRP2-mediated
efflux in MDCK-MRP2 cells (Chang et al., 1996). In nine healthy
volunteers, talinolol solution, containing either talinolol alone (50 mg),
talinolol and TPGS (0.04%), or talinolol and Poloxamer 188 (0.8%) was
administered via nasogastrointestinal tube dosing.TPGS increased AUC of
talinolol by 39% and Cmax by 100%, whereas Poloxamer 188 did not
significantly alter AUC orCmaxof talinolol. Thisin vivoobservation can be
explained by Caco-2 data showing abolishment of P-gp-mediated talinolol
efflux with TPGS (0.01%), but not Poloxamer 188 (Bogman et al., 2003).
TPGS PEG chain length was demonstrated to influence on rhodamine123
transport in Caco-2 monolayers by using TPGS analogs containing different
PEG chain length (TPGS 200/238/400/600/1000/2000/3400/3500/4000/6000
(Collnot et al., 2006)).
Pluronic P85 was also reported to cause a higher degree of alteration in the
P-gp functions than MRP2 and MRP1 in ATPase assay of P-gp, MRP1, and
MRP2 and inhibition assays with their substrates, vinblastine, and leucotriene-
C 4 (Batrakova et al., 2004). Cremophor EL (cremophor) is a nonionic
solubilizer and emulsifier used for some hydrophobic drugs and fat-soluble
vitamins. In a Phase I trial of cremophor as a 6-h infusion every 3 weeks
performed with bolus doxorubicin (50 mg/m^2 ), the AUC of doxorubicin
increased from 1448 (CV of 24%) to 1786 h^ ng/mL (CV of 15%) in the
presence of cremophor, whereas the AUC of doxorubicinol increased from 252
(CV of 42%) to 486 (CV of 22%) h^ ng/mL. Such interactions can be due to
decreased clearance of doxorubicin 612 (CV of 29%) to 477 (CV of 15%)
174 DRUG TRANSPORTERS IN DRUG DISPOSITION, DRUG INTERACTIONS