PHARMACOGENETICS AND GENOMICS Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans Background and Methods: The antiepileptic drug carbamazepine is known to be an inducer of cytochrome P450 (CYP) 3A4 after binding to the nuclear pregnane X receptor. To evaluate whether it also regulates the multidrug transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein MRP2 in humans, duodenal expression of multidrug resistance gene MDR1 messenger ribonucleic acid (mRNA) and MRP2 mRNA, content of P-gp and MRP2, and disposition of the nonmetabolized P-gp substrate talinolol after intravenous (30 mg) and long-term oral administration (100 mg for 19 days) were assessed in 7 healthy subjects (age, 23-35 years; body weight, 64-93 kg) before and after comedication of carbamazepine (600 mg for 14-18 days). Results: Carbamazepine medication was associated with increased urinary excretion of D-glucaric acid and induction of carbamazepine elimination. Creatinine clearance was not affected. Duodenal expression of both MDR1 mRNA and MRP2 mRNA and the MPR2 protein was significantly induced, whereas the P-gp content was not affected. MDR1 mRNA expression and MPR2 mRNA expression were correlated (r  0.873, P < .001). After carbamazepine, metabolic clearance of intravenous talinolol was significantly increased. Residual clearance was significantly decreased in dependence on MDR1 mRNA expression (r 0.647, P  .012) and MRP2 mRNA expression (r 0.613, P  .020). Oral absorption of talinolol was significantly lower after carbamazepine comedication (53.2%  15.5% versus 62.1%  13.0%, P  .018), and renal clearance and metabolic clearance were significantly increased, correlated in each case with MDR1 mRNA (r  0.612, P  .020, and r  0.554, P  .040, respectively) and MRP2 mRNA (r  0.596, P  .025, and r  0.565, P  .035, respectively). Conclusions: Aside from induction of CYP3A4, carbamazepine acts as an inducer of intestinal MDR1 mRNA, MRP2 mRNA, and MRP2 protein content. (Clin Pharmacol Ther 2004;76:192-200.) Thomas Giessmann, MD, Karen May, MSc, Christiane Modess, MD, Danilo Wegner, Ute Hecker, MD, Michael Zschiesche, PhD, Peter Dazert, MSc, Markus Grube, MSc, Eike Schroeder, PhD, Rolf Warzok, MD, Ingolf Cascorbi, MD, PhD, Heyo K. Kroemer, PhD, and Werner Siegmund, MD Greifswald, Germany From the Departments of Clinical Pharmacology and Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, and Departments of Internal Medicine and Pathol- ogy, University of Greifswald. This work was supported by institutional grants of the Arzneimittel- werk Dresden GmbH and the German Federal Ministry for Edu- cation and Research (grant 01 GG 9845/5, 01 ZZ 0103). Received for publication Oct 9, 2003; accepted April 16, 2004. Reprint requests: Werner Siegmund, MD, Department of Clinical Pharmacology, Ernst Moritz Arndt University, Friedrich-Loeffler- Strasse 23d, D-17487 Greifswald, Germany. E-mail: siegmuw@uni-greifswald.de 0009-9236/$30.00 Copyright © 2004 by the American Society for Clinical Pharmacology and Therapeutics. doi:10.1016/j.clpt.2004.04.011 192