P-glycoprotein and surfactants: effect on intestinal talinolol absorption.
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.
Bogman
Katrijn
K
Department of Clinical Pharmacology and Toxicology, University Hospital Basel, 4031 Basel, Switzerland.
Zysset
Yvonne
Y
Degen
Lukas
L
Hopfgartner
Gérard
G
Gutmann
Heike
H
Alsenz
Jochem
J
Drewe
Juergen
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000318:Adrenergic beta-Agonists / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D018592:Cross-Over Studies; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D010539:Permeability / Q000187:drug effects; D020442:Poloxamer / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011412:Propanolamines / Q000097:blood / Q000493:pharmacokinetics*; D013501:Surface-Active Agents / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D013501:Surface-Active Agents; D020442:Poloxamer; D014810:Vitamin E; C011550:talinolol; D011092:Polyethylene Glycols; C014225:tocophersolan