¹Departments of Clinical Pharmacology, Pharmacology, and Pharmacy, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, and Department of Internal Medicine, Department of Pathology, and Hospital Pharmacy, University of Greifswald, Greifswald, Germany

Correspondence: 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

^*This work was supported by the German Federal Ministry for Education and Research (grant 01 GG 9845/5, 01 ZZ 0103).

Received 31 July 2003; Accepted 23 October 2003.

Abstract

Background: Clinical trials have indicated that the combined - and -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.