Laurent-Kenesi M A, Funck-Brentano C, Poirier J M, Decolin D, Jaillon P
Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
Br J Clin Pharmacol. 1993 Dec;36(6):531-8. doi: 10.1111/j.1365-2125.1993.tb00411.x.
1 The metabolism of metoprolol depends in part on the genetically determined activity of the CYP2D6 isoenzyme. In vitro studies have shown that nicardipine is a potent inhibitor of CYP2D6 activity. Since the combination of metoprolol and nicardipine is likely to be used for the treatment of hypertension, we examined the interaction between these two drugs at steady-state. 2 Fourteen healthy volunteers, seven extensive and seven poor metabolisers of dextromethorphan were studied in a double-blind, randomised cross-over four-period protocol. Subjects received nicardipine 50 mg every 12 h, metoprolol 100 mg every 12 h, a combination of both drugs and placebo during 5.5 days. Steady-state pharmacokinetics of nicardipine and metoprolol were analyzed. Beta-adrenoceptor blockade was assessed as the reduction of exercise-induced tachycardia. 3 During treatment with metoprolol, alone or in combination with nicardipine, its steady-state plasma concentrations were higher in subjects of the poor metaboliser phenotype than in extensive metabolisers. Beta-adrenoceptor blockade was also more pronounced in poor metabolisers than in extensive metabolisers of dextromethorphan during treatment with metoprolol alone or in combination with nicardipine (24.0 +/- 2.4% vs 17.1 +/- 3.5% and 24.1 +/- 2.5% vs 15.4 +/- 2.7% reduction in exercise trachycardia, respectively, P < 0.01 in each case). 4 Nicardipine produced a small increase in plasma metoprolol concentration in extensive metabolisers from 35.9 +/- 16.6 to 45.8 +/- 15.4 ng ml(-1) (P < 0.02), but had no significant effect in poor metabolisers. However, nicardipine did not alter the R/S metoprolol ratio in plasma 3 h after dosing, the plasma concentration of S-(-)-metoprolol 3 h after dosing or the beta-adrenoceptor blockade produced by metoprolol in subjects of both phenotypes. The partial metabolic clearance of metoprolol to alpha-hydroxy-metoprolol was not altered significantly in extensive metabolisers. Plasma nicardipine concentration and beta-adrenoceptor blocking effects did not differ between the phenotypes and were not influenced by metoprolol. We conclude that beta-adrenoceptor blockade during repeated dosing with metoprolol is more pronounced in poor than in extensive metaboliser subjects, that nicardipine decreases a CYP2D6-independent route of metoprolol elimination but does not increase beta-adrenoceptor blockade during repeated dosing with metoprolol.
1 美托洛尔的代谢部分取决于细胞色素P450 2D6（CYP2D6）同工酶的基因决定活性。体外研究表明，尼卡地平是CYP2D6活性的强效抑制剂。由于美托洛尔和尼卡地平联合用药可能用于治疗高血压，我们研究了这两种药物在稳态时的相互作用。2 采用双盲、随机交叉四周期方案，对14名健康志愿者进行了研究，其中7名是右美沙芬的广泛代谢者，7名是右美沙芬的慢代谢者。受试者在5.5天内每12小时服用50毫克尼卡地平、每12小时服用100毫克美托洛尔、两种药物的组合以及安慰剂。分析了尼卡地平和美托洛尔的稳态药代动力学。β-肾上腺素能受体阻滞通过运动诱发心动过速的降低来评估。3 在单独使用美托洛尔或与尼卡地平联合使用的治疗过程中，慢代谢者表型受试者的美托洛尔稳态血浆浓度高于广泛代谢者。在单独使用美托洛尔或与尼卡地平联合使用的治疗过程中，右美沙芬慢代谢者的β-肾上腺素能受体阻滞也比广泛代谢者更明显（运动性心动过速的降低分别为24.0±2.4%对17.1±3.5%和24.1±2.5%对15.4±2.7%，每种情况P<0.01）。4 尼卡地平使广泛代谢者的血浆美托洛尔浓度从35.9±16.6纳克/毫升小幅升至45.8±15.4纳克/毫升（P<0.02），但对慢代谢者无显著影响。然而，尼卡地平并未改变给药后3小时血浆中美托洛尔的R/S比值、给药后3小时S-（-）-美托洛尔的血浆浓度或两种表型受试者中美托洛尔产生的β-肾上腺素能受体阻滞。在广泛代谢者中，美托洛尔向α-羟基美托洛尔的部分代谢清除率没有显著改变。血浆尼卡地平浓度和β-肾上腺素能受体阻滞作用在两种表型之间没有差异，也不受美托洛尔的影响。我们得出结论，在重复服用美托洛尔期间，慢代谢者的β-肾上腺素能受体阻滞比广泛代谢者更明显，尼卡地平减少了美托洛尔不依赖CYP2D6的消除途径，但在重复服用美托洛尔期间并未增加β-肾上腺素能受体阻滞。
