Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2000) 68, 345–355; doi: 10.1067/mcp.2000.109797
Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction*
Kristin Westphal MD1,2, Anita Weinbrenner MD1,2, Michael Zschiesche PhD1,2, Gerd Franke PhD1,2, Manfred Knoke MD1,2, Reinhard Oertel PhD1,2, Peter Fritz MD1,2, Oliver von Richter PhD1,2, Rolf Warzok MD1,2, Thomas Hachenberg MD1,2, Hans-Martin Kauffmann MD1,2, Dieter Schrenk MD1,2, Bernd Terhaag MD1,2, Heyo K. Kroemer PhD1,2 and Werner Siegmund MD1,2
- 1Institute of Pharmacology, Ernst Moritz Arndt University.
- 2Departments of Internal Medicine A, Pathology, Anesthesiology and Intensive Care, University of Greifswald, Greifswald, Germany; Institute of Pathology, Robert Bosch Hospital, Stuttgart, Germany; Institute of Clinical Pharmacology, University of Technology, Dresden, Germany; Institute of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Germany; Arzneimittelwerk Dresden GmbH,Dresden, Germany; Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
Correspondence: Werner Siegmund, MD, Institute of Pharmacology, Ernst Moritz Arndt University, Friedrich Loefflerstr. 23d, D-17487 Greifswald, Germany E-mail: siegmuw@mail.uni-greifswald.de
*Supported by Arzneimittelwerk Dresden GmbH, Dresden, Germany.
Presented in part at the 100th ASCPT meeting, San Antonio, Texas, March 18-20, 1999.
Received 6 April 2000; Accepted 29 June 2000.
Abstract
Background: P-Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P-glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P-glycoprotein substrate talinolol, a 
1-blocker without appreciable metabolic disposition but intense intestinal secretion in human beings.
Methods: Pharmacokinetics of talinolol (a single dose of 30 mg administered intravenously or 100 mg administered orally for 7 days) and duodenal expression of the MDR1 gene product P-glycoprotein as assessed by reverse transcriptase-polymerase chain reaction of the MDR1–messenger ribonucleic acid, by immunohistochemistry and Western blot analysis were analyzed before and after coadministration of rifampin (600 mg per day for 9 days) in 8 male healthy volunteers (age 22 to 26 years).
Results: During rifampin treatment, the areas under the curve of intravenous and oral talinolol were significantly lower (21% and 35%; P < .05). Treatment with rifampin resulted in a significantly increased expression of duodenal P-glycoprotein content 4.2-fold (2.9, 6.51) (Western blot) and messenger RNA was increased in six of the eight volunteers. P-Glycoprotein expression in biopsy specimens of gut mucosa correlated significantly with the systemic clearance of intravenous talinolol (rs = 0.74; P < .001).
Conclusions: Rifampin induces P-glycoprotein–mediated excretion of talinolol predominantly in the gut wall. Moreover, clearance of talinolol from the blood into the lumen of the gastrointestinal tract may be predicted by the individual intestinal P-glycoprotein expression. Thus we describe a new type of steady-state drug interaction affecting compounds that are subject to transport rather than metabolism. (Clin Pharmacol Ther 2000;68:345-55.)
