Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration- and dose-dependent absorption in vitro and in vivo.
OBJECTIVE
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.
Wetterich
U
U
Department of Pharmacology, Johann Wolfgang Goethe-University, Biocenter Niederursel, Frankfurt/Main, Germany.
Spahn-Langguth
H
H
Mutschler
E
E
Terhaag
B
B
Rösch
W
W
Langguth
P
P
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D000704:Analysis of Variance; D001659:Biliary Tract / Q000378:metabolism; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002763:Cholecystectomy; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D011412:Propanolamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; C011550:talinolol