| Autor: |
Giessmann, Thomas, May, Karen, Modess, Christiane, Wegner, Danilo, Hecker, Ute, Zschiesche, Michael, Dazert, Peter, Grube, Markus, Schroeder, Eike, Warzok, Rolf, Cascorbi, Ingolf, Kroemer, Heyo K., Siegmund, Werner |
| Zdroj: |
Clinical Pharmacology & Therapeutics; September 2004, Vol. 76 Issue: 3 p192-200, 9p |
| Abstrakt: |
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.Clinical Pharmacology & Therapeutics (2004) 76, 192–200; doi: 10.1016/j.clpt.2004.04.011 |
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