Stereoselective metabolism of metoprolol in Caucasians and Nigerians‐ relationship to debrisoquine oxidation phenotype.

Lennard,; Tucker, GT; Woods, Helen Buckley; Silas, J H; Iyun, AO

doi:10.1111/j.1365-2125.1989.tb03424.x

Cited by 12 publications

(6 citation statements)

References 8 publications

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“…The S/R metoprolol ratios were also found to vary between genotypes, at 1.6, 1.3 and 1.0 for two, one and zero functional alleles, respectively. These findings support the earlier observation in healthy volunteers of stereoselective metabolism of metoprolol, 24,25 suggesting that R-metoprolol is more dependent on CYP2D6 for metabolism than S-metoprolol. In only one of the patient studies, 15 R-metoprolol concentrations were measured and these were not reported specifically.…”

Section: Discussionsupporting

confidence: 82%

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

et al. 2009

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The aims of this study were to examine the relationships between CYP2D6 genotype and metoprolol dose, S-and R-metoprolol concentrations and clinical effects in patients with systolic heart failure. Data were obtained for 52 subjects, of which 27 had 2 functional alleles (24/27, CYP2D6*1/*1), 22 had 1 functional allele (18/22, CYP2D6*1/*4) and 3 had no functional alleles (CYP2D6*4/*4). Median dose-adjusted concentrations of S-metoprolol (active) were 6.3-and 3.2-fold higher in subjects with zero or one functional allele (P ¼ 0.016 and P ¼ 0.006), respectively, compared with subjects with two functional alleles. For the R-enantiomer (inactive), these concentrations were 10.7-and 3.7-fold higher (P ¼ 0.013 and P ¼ 0.003), respectively. Despite clear gene-concentration differences, no relationships between CYP2D6 genotype and dose or clinical effects could be shown. Although the number with no functional alleles was too small (n ¼ 3) to show effects, in patients with 1 functional allele other sources of variance are likely to be obscuring differences in clinical effects.

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Section: Discussionsupporting

confidence: 82%

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

et al. 2009

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“…32,36,37 In Nigerian and South African populations, however, poor debrisoquine metabolizers were not phenotyped as poor metoprolol metabolizers. 19 The results showed enantioselectivity in the pharmacokinetics of metoprolol, with observation of higher areas under the plasma concentration versus time curves for (S)-metoprolol compared to its antipode (P < .05) as consequence of a lower Cl T /f for this enantiomer, and resulted in mean AUC (S)-/AUC (R)-ratios of 1.21. Enantiomeric ratios of 1.39 were reported by Johnson and Burlew 5 in the investigation of healthy volunteers treated with a single dose of racemic metoprolol, and ratios of 1.29 were reported by Cerqueira et al 8 somes.…”

Section: Discussionmentioning

confidence: 88%

“…CYP2D6 genotype‐phenotype correlates with differences in metoprolol pharmacokinetics 17 . In addition to the oxidative phenotype, enantioselectivity in the pharmacokinetics of metoprolol administered orally to extensive metabolizers (EM) is highly relevant in terms of the wide interindividual variability observed in the kinetic disposition of this drug 6 , 8 , 18 , 19 . It is known that genetic factors play a preponderant role in stereoselectivity; however, the influence of diseases has been surprisingly little investigated.…”

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confidence: 99%

Influence of Chronic Renal Failure on Stereoselective Metoprolol Metabolism in Hypertensive Patients

Cerqueira

Coelho

Geleilete

et al. 2005

The Journal of Clinical Pharma

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The influence of chronic renal failure on the stereoselective metabolism of rac-metoprolol was investigated in 15 hypertensive patients, 7 of them with chronic renal failure and 8 with normal renal function. They were treated with rac-metoprolol (200 mg) for 7 days. The patients of both groups presented stereoselectivity in metoprolol metabolism, favoring the formation of 1'R-alpha-hydroxymetoprolol (AUC(1(')R/1(')S)(0-24) approximately 2.5) and (R)-metoprolol acidic metabolite (AUC((S)/(R))(0-24) = 0.8), the latter resulting in the plasma accumulation of (S)-metoprolol (AUC((S)/(R))(0-24) = 1.2). Patients with chronic renal failure presented plasma accumulation of the 4 alpha-hydroxymetoprolol isomers and of both metoprolol acidic metabolite enantiomers. A 50% reduction in Cl(R) does not explain the 3- to 4-fold plasma accumulation of metoprolol acidic metabolite in this group, suggesting that other pathways of metoprolol elimination are affected in chronic renal failure in addition to renal excretion. Chronic renal failure does not change the stereoselective kinetic disposition of metoprolol but modifies its stereoselective metabolism, inducing some of the CYP enzymes involved in the formation of the metoprolol acid metabolite.

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“…Approximately 70% of the total metabolism of metoprolol (O-demethylation and ahydroxylation) is dependent on CYP2D6 [26]. Earlier studies have shown that PM individuals have higher plasma metoprolol concentrations than EMs when given standard doses of the drug [27], the S/R ratio of metoprolol enantiomers is lower in PMs since the concentration of the inactive R-metoprolol is increased more clearly [28]. Koytchev et al [29] studied the in¯uence of the CYP2D6*4 allele on the pharmacokinetics of controlled-release metoprolol.…”

Section: B-adrenoceptormentioning

confidence: 99%

Influence of hydroxychloroquine on the bioavailability of oral metoprolol

Somer

Kallio

Pesonen

et al. 2000

Brit J Clinical Pharma

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Aims Hydroxychloroquine (HCQ) is used widely in the treatment of chronic in¯ammatory diseases such as rheumatoid arthritis. Since there is great interindividual variability in the pharmacokinetics of HCQ and chloroquine is a potent inhibitor of CYP2D6-catalysed pathways in vitro, we wished to study the interaction of HCQ with CYP2D6-mediated metabolism of other drugs in vivo. Methods Metoprolol and dextromethorphan (DM) were selected as probe drugs because they are well-studied and widely used test substrates of CYP2D6. In this randomized, double-blind crossover study, seven healthy volunteers with extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxychloroquine or placebo daily for 8 days after which single oral dose pharmacokinetics of metoprolol were investigated. Dextromethorphan metabolic ratio (DM-MR) was also determined at baseline and after the ingestion of HCQ or placebo. Results Concomitant administration of HCQ increased the bioavailability of metoprolol, as indicated by signi®cant increases in the area under the plasma concentration-time curve (65t4.6%) and maximal plasma concentrations (72t6.9%) of metoprolol. While the DM-MR values were not signi®cantly changed, the phenotypic classi®cation of one individual, who was heterozygous for a mutant CYP2D6 allele, was converted to a poor metabolizer by HCQ administration. Conclusions HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6. The inhibitory effect of HCQ on dextromethorphan metabolism was not apparent when DM-MR was used as an indicator, except in an individual with limited CYP2D6 capacity.

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Stereoselective metabolism of metoprolol in Caucasians and Nigerians‐ relationship to debrisoquine oxidation phenotype.

Cited by 12 publications

References 8 publications

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure

Influence of Chronic Renal Failure on Stereoselective Metoprolol Metabolism in Hypertensive Patients

Influence of hydroxychloroquine on the bioavailability of oral metoprolol

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