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

Background Clinical trials have indicated that the combined β- and α-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. Clinical Pharmacology & Therapeutics (2004) 75, 213–222; doi: 10.1016/j.clpt.2003.10.004