INFLUENCE OF CYP2D6-DEPENDENT METABOLISM ON THE STEADY-STATE PHARMACOKINETICS AND PHARMACODYNAMICS OF METOPROLOL AND NICARDIPINE, ALONE ANDIN COMBINATION

1 The metabolism of metoprolol depends in part on the genetically dete rmined activity of the CYP2D6 isoenzyme. In vitro studies have shown t hat nicardipine is a potent inhibitor of CYP2D6 activity. Since the co mbination of metoprolol and nicardipine is likely to be used for the t reatment of hypertension, we examined the interaction between these tw o drugs at steady-state. 2 Fourteen healthy volunteers, seven extensiv e and seven poor metabolisers of dextromethorphan were studied in a do uble-blind, randomised cross-over four-period protocol. Subjects recei ved nicardipine 50 mg every 12 h, metoprolol 100 mg every 12 h, a comb ination of both drugs and placebo during 5.5 days. Steady-state pharma cokinetics of nicardipine and metoprolol were analyzed. Beta-adrenocep tor blockade was assessed as the reduction of exercise-induced tachyca rdia. 3 During treatment with metoprolol, alone or in combination with nicardipine, its steady-state plasma concentrations were higher in su bjects of the poor metaboliser phenotype than in extensive metaboliser s. Beta-adrenoceptor blockade was also more pronounced in poor metabol isers than in extensive metabolisers of dextromethorphan during treatm ent 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 Nicardi pine produced a small increase in plasma metoprolol concentration in e xtensive 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, n icardipine 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 o f both phenotypes. The partial metabolic clearance of metoprolol to al pha-hydroxy-metoprolol was not altered significantly in extensive meta bolisers. 5 Plasma nicardipine concentration and beta-adrenoceptor blo cking effects did not differ between the phenotypes and were not influ enced by metoprolol. 6 We conclude that beta-adrenoceptor blockade dur ing repeated dosing with metoprolol is more pronounced in poor than in extensive metaboliser subjects, that nicardipine decreases a CYP2D6-i ndependent route of metoprolol elimination but does not increase beta- adrenoceptor blockade during repeated dosing with metoprolol.