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P-glycoprotein and surfactants: effect on intestinal talinolol absorption

Bogman, Katrijn
Zysset, Yvonne
Degen, Lukas
Gutmann, Heike
Alsenz, Jochem
Drewe, Juergen
Published in Clinical Pharmacology and Therapeutics. 2005, vol. 77, no. 1, p. 24-32
Abstract 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-alpha-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-infinity ) 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-infinity 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.
Keywords Adrenergic beta-Agonists/blood/pharmacokineticsAdultArea Under CurveBiological AvailabilityCaco-2 CellsCross-Over StudiesDrug InteractionsHalf-LifeHumansIntestinal Absorption/drug effectsMaleP-Glycoprotein/antagonists & inhibitorsPermeability/drug effectsPoloxamer/pharmacologyPolyethylene Glycols/pharmacologyPropanolamines/blood/pharmacokineticsSurface-Active Agents/pharmacologyVitamin E/analogs & derivatives/pharmacology
PMID: 15637528
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BOGMAN, Katrijn et al. P-glycoprotein and surfactants: effect on intestinal talinolol absorption. In: Clinical Pharmacology and Therapeutics, 2005, vol. 77, n° 1, p. 24-32. doi: 10.1016/j.clpt.2004.09.001 https://archive-ouverte.unige.ch/unige:2374

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Deposited on : 2009-08-10

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