Influence of CYP2D6‐dependent metabolism on the steady‐state pharmacokinetics and pharmacodynamics of metoprolol and nicardipine, alone and in combination

Abstract

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 fourperiod 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. 13-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. 3-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-' (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 3-adrenoceptor blockade produced by metoprolol in subjects of both phenotypes. The partial metabolic clearance of metoprolol to oL-hydroxy-metoprolol was not altered significantly in extensive metabolisers. 5 Plasma nicardipine concentration and 13-adrenoceptor blocking effects did not differ between the phenotypes and were not influenced by metoprolol.6 We conclude that 13-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 ,3-adrenoceptor blockade during repeated dosing with metoprolol.

Enantioselectivity in the steady-state pharmacokinetics of metoprolol in hypertensive patients

“…We used the debrisoquine metabolic ratio % of dose excreted as debrisoquine/% of dose excreted as 4-hydroxydebrisoquine less than 12.6 to classify our subjects as extensive metabolizers (EM), considering that 70-80% of metoprolol metabolism is mediated via the genetically determined activity of CYP2D6 and that poor metabolizers (PM) show loss of stereoselective metabolism of both enantiomers of metoprolol. [9][10][11][12] In our study, debrisoquine metabolic ratios varied widely among the hypertensive patients, ranging from 0.28 to 6.56.…”

“…routes to healthy volunteers. 7,8,11,12 9 respectively. In the present investigation, the influence of hypertension on the enantioselective pharmacokinetics of metoprolol was evaluated in the steady-state over a 24 h dose interval.…”

“…This property suggests clinical relevance of the investigation of enantioselectivity in the disposition of metoprolol. 2,8,9 Clinical studies by Lennard et al (1983), 12 Jonkers et al (1991), 8 and Johnson and Burlew (1996) 7 have reported that metoprolol kinetics are stereoselective in healthy volunteers receiving a single oral dose of racemic metoprolol. Stereoselectivity has also been reported at steady-state, with higher plasma concentrations of (−)-(S)-metoprolol than (+)-(R)-metoprolol and in in vitro studies of oxidative metabolism of metoprolol in human liver microsomes.…”

“…Stereoselectivity has also been reported at steady-state, with higher plasma concentrations of (−)-(S)-metoprolol than (+)-(R)-metoprolol and in in vitro studies of oxidative metabolism of metoprolol in human liver microsomes. 1,9,14,15 Patients with the poor metabolizer phenotype show loss of stereoselective metabolism of the enantiomers of metoprolol and therefore show higher concentrations of both enantiomers. 8 The route of administration is also relevant in the manifestation of enantioselectivity.…”

Stereoselective analysis of flecainide enantiomers using reversed‐phase liquid chromatography for assessing CYP2D6 activity

“…Stereoselective analysis may not be useful for assessments of flecainide efficacy and safety because enantiomers have similar electrophysiologic activities in canine cardiac Purkinje fibers in vitro and animal models (Banitt et al, 1986;Kroemer et al, 1989). In contrast, S/R ratios in serum flecainide concentration may reflect CYP2D6 activity as well as the case of mephenytoin on CYP2C19 activity, and metoprolol and mianserin on CYP2D6 activity (Laurent-Kenesi et al, 1993;Dahl et al, 1994;Brockmöller et al, 1995). The present results suggest that stereoselective analyses of flecainide provide information on CYP2D6 activity without genotyping lots of single nucleotide polymorphisms affecting the enzyme activity.…”