¹Department of Clinical Pharmacology and Toxicology, University Hospital Basel, and Preclinical Research Department, F. Hoffmann-La Roche Ltd, Basel, and Life Sciences Mass Spectrometry Group, Laboratory of Pharmaceutical Analytical Chemistry, School of Pharmacy, University of Geneva, Geneva

Correspondence: Juergen Drewe, MD, MSc, Department of Clinical Pharmacology & Toxicology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland E-mail: Juergen.Drewe@unibas.ch

Received 16 April 2004; Accepted 2 September 2004.

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--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.