title: Stereoselective disposition of talinolol in man.
abstract: The disposition of the beta-blocking drug talinolol is controlled by P-glycoprotein in man. Because talinolol is marketed as a racemate, we reevaluated the serum-concentration time profiles of talinolol of a previously published study with single intravenous (30 mg) and repeated oral talinolol (100 mg for 14 days) before and after comedication of rifampicin (600 mg per day for 9 days) in eight male healthy volunteers (age 22-26 years, body weight 67-84 kg) with respect to differences in the kinetic profiles of the two enantiomers S(-) talinolol and R(+) talinolol. Additionally, the metabolism of talinolol in human liver microsomes was examined. After oral administration, S(-) talinolol was slightly less absorbed and faster eliminated than R(+) talinolol. The absolute bioavailabilty of the R(+) enantiomer of talinolol was slightly but significantly higher than of its S(-) enantiomer. Coadministration of rifampicin further intensified this difference in the disposition of R(+) and S(-) talinolol (p < 0.05). Formation of 4-trans hydroxytalinolol was the major metabolic pathway in human liver microsomes. All Cl(int) values of S(-) were higher than of R(+) talinolol; 0.1 microM ketoconazole inhibited the formation of all metabolites. In conclusion, the stereoselectivity of talinolol disposition is of minor importance, and most likely caused by presystemic biotransformation via CYP3A4. The less active R(+) talinolol might be suitable for phenotyping P-glycoprotein expression in man.
authors.affiliation: Department of Pharmacology, Ernst Moritz Arndt University, Friedrich Loeffler Strasse 23d, D-17487 Greifswald, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zschiesche
authors.forename: Girum Lakew
authors.initials: GL
authors.lastname: Lemma
authors.forename: Klaus-Jürgen
authors.initials: KJ
authors.lastname: Klebingat
authors.forename: Gerd
authors.initials: G
authors.lastname: Franke
authors.forename: Bernd
authors.initials: B
authors.lastname: Terhaag
authors.forename: Anna
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Gramatté
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D011412:Propanolamines / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D012293:Rifampin / Q000493:pharmacokinetics; D018709:Statistics, Nonparametric
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D011412:Propanolamines; C011550:talinolol; D012293:Rifampin