title: Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Peter Holtz Reaearch Center of Pharmacology & Experiental Therapeutics, University of Greifswald, Friedrich-Loeffler-Strasse 23d, D-17487 Greifswald, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Giessmann
authors.forename: Karen
authors.initials: K
authors.lastname: May
authors.forename: Christiane
authors.initials: C
authors.lastname: Modess
authors.forename: Danilo
authors.initials: D
authors.lastname: Wegner
authors.forename: Ute
authors.initials: U
authors.lastname: Hecker
authors.forename: Michael
authors.initials: M
authors.lastname: Zschiesche
authors.forename: Peter
authors.initials: P
authors.lastname: Dazert
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Eike
authors.initials: E
authors.lastname: Schroeder
authors.forename: Rolf
authors.initials: R
authors.lastname: Warzok
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
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 / Q000235:genetics*; D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011412:Propanolamines / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011412:Propanolamines; C000715087:ABCC2 protein, human; C011550:talinolol; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human