Vercruysse I, Schoors D F, Massart D L, Dupont A G
Department of Pharmacology, Vrije Universiteit Brussels (VUB), Belgium.
Cardiovasc Drugs Ther. 1993 Aug;7(4):721-6. doi: 10.1007/BF00877826.
To determine the effect of dihydropyridines on the metabolism of propranolol, we studied the effects of a single oral dose of nicardipine, nifedipine, and BAY-K-8644 on the pharmacokinetics of propranolol in male Wistar rats fitted with a catheter in the jugularis vein. Oral propranolol (15 mg/kg and 1.5 mg/kg) and intravenous propranolol (1.5 mg/kg) were administered either alone or together with oral nicardipine (2.5 mg/kg). Oral propranolol (15 mg/kg) was administered with oral nifedipine (1.5 mg/kg) and with oral BAY-K-8644 (1.5 mg/kg). Nicardipine increased significantly the AUC and Cmax of oral propranolol (1.5 mg/kg and 15 mg/kg). However, the plasma concentration time curve of intravenous propranolol (1.5 mg/kg) was unaffected. Nifedipine also significantly increased the AUC and Cmax of oral propranolol (15 mg/kg), whereas with BAY-K-8644 there was only a slight increase in the bioavailability of oral propranolol (15 mg/kg). The results indicate that the dihydropyridine calcium antagonists decrease the metabolism of propranolol as a result of a decrease in first-pass clearance. Although an interaction at the level of cytochrome P450 may also be involved, the results of the present study suggest that the inhibitory effect can be largely attributed to changes in liver blood flow.
为了确定二氢吡啶类药物对普萘洛尔代谢的影响，我们研究了单次口服尼卡地平、硝苯地平和BAY-K-8644对颈静脉插管的雄性Wistar大鼠体内普萘洛尔药代动力学的影响。单独或与口服尼卡地平（2.5mg/kg）一起给予口服普萘洛尔（15mg/kg和1.5mg/kg）以及静脉注射普萘洛尔（1.5mg/kg）。口服普萘洛尔（15mg/kg）与口服硝苯地平（1.5mg/kg）以及口服BAY-K-8644（1.5mg/kg）一起给药。尼卡地平显著增加了口服普萘洛尔（1.5mg/kg和15mg/kg）的AUC和Cmax。然而，静脉注射普萘洛尔（1.5mg/kg）的血浆浓度-时间曲线未受影响。硝苯地平也显著增加了口服普萘洛尔（15mg/kg）的AUC和Cmax，而对于BAY-K-8644，口服普萘洛尔（15mg/kg）的生物利用度仅略有增加。结果表明，二氢吡啶类钙拮抗剂由于首过清除率降低而减少了普萘洛尔的代谢。虽然可能也涉及细胞色素P450水平的相互作用，但本研究结果表明，抑制作用在很大程度上可归因于肝血流量的变化。
