Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration- and dose-dependent absorption in vitro and in vivo

Pharm Res. 1996 Apr;13(4):514-22. doi: 10.1023/a:1016029601311.

Abstract

Purpose: To evaluate carrier-mediated intestinal secretion of talinolol enantiomers in vivo and in vitro.

Methods: In clinical studies with i.v. and p.o. dosage of rac-talinolol (30 mg and 100 mg, resp.) performed in a small number of cholecystectomized patients total and partial clearances were determined on the basis of plasma, bile and urine concentrations. The dose-dependence of AUC was investigated in 12 healthy volunteers (25, 50, 100, and 400 mg rac-talinolol as single p.o. doses). Concentration-dependence of the permeability across Caco-2 cell monolayers included concentrations from 0.1 to 2.0 mM, inhibition by verapamil was tested at 0.5 mM.

Results: The total clearance as well as the apparent oral clearance (CL/F) were slightly higher for S-(-)- than for R-(+)-talinolol. Calculation of the partial clearances showed that also the residual clearance was higher for the S- than for the R-enantiomer. In the healthy volunteers, CL/F increased with increasing doses, while the S/R ratio decreased approaching unity for the highest dose. Also the results from Caco-2 cell permeation studies yielded a clear concentration-dependence with decreasing stereoselectivity for the higher concentration range. Permeability of both enantiomers was considerably higher for b-->a than a-->b transport, however, this difference disappeared when verapamil was added.

Conclusions: Although not very expressed, the detected stereoselectivities indicate a preferential absorption of R-(+)-talinolol in a lower concentration and dose range, which is most probably due to a moderate stereoselectivity at the carrier system involved in intestinal secretion.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adrenergic beta-Antagonists / administration & dosage
  • Adrenergic beta-Antagonists / blood
  • Adrenergic beta-Antagonists / pharmacokinetics*
  • Adrenergic beta-Antagonists / urine
  • Adult
  • Analysis of Variance
  • Biliary Tract / metabolism
  • Biological Availability
  • Caco-2 Cells
  • Cell Membrane Permeability / drug effects
  • Cholecystectomy
  • Chromatography, High Pressure Liquid
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Humans
  • Injections, Intravenous
  • Intestinal Absorption / physiology*
  • Intestinal Mucosa / metabolism*
  • Kidney / metabolism
  • Male
  • Metabolic Clearance Rate
  • Propanolamines / administration & dosage
  • Propanolamines / blood
  • Propanolamines / pharmacokinetics*
  • Propanolamines / urine
  • Stereoisomerism

Substances

  • Adrenergic beta-Antagonists
  • Propanolamines
  • talinolol