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P‐Glycoprotein and Surfactants: Effect on Intestinal Talinolol Absorption
Author(s) -
Bogman Katrijn,
Zysset Yvonne,
Degen Lukas,
Hopfgartner Gérard,
Gutmann Heike,
Alsenz Jochem,
Drewe Juergen
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.09.001
Subject(s) - bioavailability , poloxamer , chemistry , pharmacology , pharmacokinetics , in vivo , absorption (acoustics) , pulmonary surfactant , chromatography , materials science , medicine , biochemistry , microbiology and biotechnology , organic chemistry , composite material , copolymer , biology , polymer
Background and Objective Surfactants used in pharmaceutical formulations can modulate drug absorption by multiple mechanisms including inhibition of intestinal P‐glycoprotein (P‐gp). Our objective was to analyze the effect of 2 surfactants with different affinity for P‐gp in vitro on the intestinal absorption and bioavailability of the P‐gp substrate talinolol in humans. Methods In vitro, the influence of surfactants on talinolol permeability was studied in Caco‐2 cells. In vivo, an open‐label 3‐way crossover study with 9 healthy male volunteers was performed. Subjects were intubated with a 1‐lumen nasogastrointestinal tube. The study solution, containing either talinolol (50 mg), talinolol and D ‐α‐tocopheryl polyethylene glycol 1000 succinate (TPGS) (0.04%), or talinolol and Poloxamer 188 (0.8%), was administered through the tube. Results TPGS, but not Poloxamer 188, inhibited the P‐gp‐mediated talinolol transport in Caco‐2 cells. In healthy volunteers TPGS increased the area under the plasma concentration‐time curve with extrapolation to infinity (AUC 0‐∞ ) of talinolol by 39% (90% confidence interval, 1.10–1.75) and the maximum plasma concentration (C max ) by 100% (90% confidence interval, 1.39–2.88). Poloxamer 188 did not significantly alter the AUC 0‐∞ or C max of talinolol. Conclusions This in vivo intraduodenal perfusion study showed that low concentrations of TPGS, close to the concentrations that showed P‐gp inhibition in vitro, significantly increased the bioavailability of talinolol. The study design excluded modulation of solubility by TPGS and unspecific surfactant‐related effects. The latter was supported by the absence of modulation of the talinolol pharmacokinetics by Poloxamer 188, which does not modulate P‐gp. Therefore we consider intestinal P‐gp inhibition by TPGS as the major underlying mechanism for the increase in talinolol bioavailability. Clinical Pharmacology & Therapeutics (2005) 77 , 24–32; doi: 10.1016/j.clpt.2004.09.001