CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects

Clin Pharmacol Ther. 2004 Mar;75(3):213-22. doi: 10.1016/j.clpt.2003.10.004.

Abstract

Background: Clinical trials have indicated that the combined beta- and alpha-adrenergic receptor blocker carvedilol improves the survival rate in patients with advanced chronic heart failure. The objective of our study was the identification and quantification of factors that modulate steady-state serum concentrations of carvedilol and its enantiomers and that may influence therapeutic efficacy and safety.

Methods: The influence of genetic variants of cytochrome P450 (CYP) 2D6 and CYP2C9 and of transporter proteins (P-glycoprotein, multidrug resistance protein 2 [MRP2]) on the disposition of carvedilol and its enantiomers after intravenous (5 mg) and long-term oral administration (25 mg for 7 days) was assessed in 12 healthy subjects. The intestinal expression of P-glycoprotein and MRP2 was analyzed by quantitative real-time polymerase chain reaction and immunohistochemical techniques.

Results: The area under the serum concentration-time curve (AUC) values of carvedilol were significantly (P <.05) increased in 6 subjects with CYP2D6 deficiency, with effects being more pronounced for R(+)-carvedilol (230 +/- 72.6 ng. h/mL versus 93.9 +/- 64.6 ng. h/mL in extensive metabolizers) than for S(-)-carvedilol (62.9 +/- 21.1 ng. h/mL versus 32.7 +/- 14.5 ng. h/mL). The AUC and fecal excretion of intravenous carvedilol were correlated with the intestinal expression of MDR1 messenger ribonucleic acid (mRNA) (r = -0.67, P =.001; r = 0.83, P =.002) and MRP2 mRNA (r = -0.74, P <.001; r = 0.70, P =.025). Furthermore, we measured the disposition of long-term oral carvedilol after comedication of the pregnane X receptor ligand rifampin (INN, rifampicin) (600 mg, 9 days), which up-regulates both P-glycoprotein and MRP2 but not CYP2D6. Rifampin decreased the AUC of carvedilol to an extent independent of the CYP2D6 genotype (poor metabolizers, 341 +/- 147 ng. h/mL versus 126 +/- 41.7 ng. h/mL; extensive metabolizers, 173 +/- 102 ng. h/mL versus 74 +/- 41.4 ng. h/mL; both P <.05). The AUC was significantly correlated with intestinal expression of MDR1 mRNA (r = -0.671, P =.001) and MRP2 mRNA (r = -0.595, P <.006).

Conclusions: Variable plasma concentrations of carvedilol during long-term administration are predicted by CYP2D6 genotype and intestinal expression of P-glycoprotein and MRP2.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Adult
  • Analysis of Variance
  • Area Under Curve
  • Carbazoles / administration & dosage
  • Carbazoles / blood*
  • Carvedilol
  • Cytochrome P-450 CYP2D6 / genetics*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Duodenum / drug effects
  • Duodenum / metabolism
  • Female
  • Genetic Variation / drug effects
  • Genetic Variation / physiology
  • Genotype
  • Humans
  • Male
  • Membrane Transport Proteins / biosynthesis*
  • Membrane Transport Proteins / genetics
  • Metabolic Clearance Rate / drug effects
  • Metabolic Clearance Rate / physiology
  • Multidrug Resistance-Associated Proteins / biosynthesis*
  • Multidrug Resistance-Associated Proteins / genetics
  • Predictive Value of Tests
  • Propanolamines / administration & dosage
  • Propanolamines / blood*
  • Rifampin / pharmacology*
  • Statistics, Nonparametric

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carbazoles
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Propanolamines
  • Carvedilol
  • multidrug resistance-associated protein 2
  • Cytochrome P-450 CYP2D6
  • Rifampin