Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans

Clin Pharmacol Ther. 2004 Sep;76(3):192-200. doi: 10.1016/j.clpt.2004.04.011.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • Adult
  • Anticonvulsants / pharmacology*
  • Carbamazepine / pharmacology*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Female
  • Gene Expression Regulation / drug effects*
  • Humans
  • Intestinal Mucosa / metabolism*
  • Male
  • Membrane Transport Proteins / genetics*
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics*
  • Propanolamines / pharmacokinetics*


  • ABCC2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anticonvulsants
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Propanolamines
  • Carbamazepine
  • talinolol
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human