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Title

P-glycoprotein and surfactants: effect on intestinal talinolol absorption

Authors
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
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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. https://archive-ouverte.unige.ch/unige:2374

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Deposited on : 2009-08-10

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