| Autor: |
Giessmann, Thomas, Modess, Christiane, Hecker, Ute, Zschiesche, Michael, Dazert, Peter, Kunert-Keil, Christiane, Warzok, Rolf, Engel, Georg, Weitschies, Werner, Cascorbi, Ingolf, Kroemer, Heyo K., Siegmund, Werner |
| Zdroj: |
Clinical Pharmacology & Therapeutics; March 2004, Vol. 75 Issue: 3 p213-222, 10p |
| Abstrakt: |
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 |
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