Evidence for Intestinal Secretion as an Additional Clearance Pathway of Talinolol Enantiomers: Concentration- and Dose-dependent Absorption in Vitro and in Vivo |
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Authors: | Wetterich Ulrike Spahn-Langguth Hildegard Mutschler Ernst Terhaag Bernd Rösch Wolfgang Langguth Peter |
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Institution: | (1) Department of Pharmacology, Johann Wolfgang Goethe-University Biocenter N.ederursel, Marie-Curie-Str. 9, Bldg. N 260, 60439 Frankfurt/Main, Germany;(2) Arzneimittelwerk Dresden GmbH, Mei ner Stra e 35, 01445 Radebeul, Germany;(3) Nordwest-Krankenhaus, Steinbacher Hohl 2-26, 60488 Frankfurt/Main, Germany;(4) Present address: Department of Pharmaceutical Chemistry, Martin-Luther-University, Weinbergweg 15, 06120 Halle/Saale (present address);(5) Department of Pharmacy, ETH-Zürich, Winterthurer Str. 190, 8057 Zürich, Switzerland |
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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. |
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Keywords: | intestinal secretion intestinal absorption bioavailability non-linear pharmacokinetics stereoselectivity enantiomers beta-adrenoceptor antagonists talinolol |
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