Metoprolol ?-hydroxylation is a poor probe for debrizoquine oxidation (CYP2D6) polymorphism in Jordanians

Al-Hadidi, H. F.; Irshaid, Yacoub M.; Rawashdeh, N. M.

doi:10.1007/bf00191160

Cited by 11 publications

(3 citation statements)

References 17 publications

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“…Sedation, rapid S ‐mephenytoin metabolism, and questionable urinary stability of individual enantiomers have limited the utility of mephenytoin as a CYP2C19 probe 28 , 29 , 30 , 31 . Several studies have suggested that metoprolol α‐hydroxylation may not cosegregate with the metabolism of other CYP2D6 probes in some nonwhite populations, questioning its value as a CYP2D6 probe 32 , 33 , 34 . Debrisoquin, a valid CYP2D6 probe, is not approved for use by the Food and Drug Administration and, as a result, has limited availability in the United States.…”

Section: Discussionmentioning

confidence: 99%

Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N -acetyltransferase-2, and xanthine oxidase with the ″Cooperstown cocktail”

Streetman

Bleakley

Kim

et al. 2000

Clinical Pharmacology & Therapeutics

127

120

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Section: Discussionmentioning

confidence: 99%

Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N -acetyltransferase-2, and xanthine oxidase with the ″Cooperstown cocktail”

Streetman

Bleakley

Kim

et al. 2000

Clinical Pharmacology & Therapeutics

127

120

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“…Failure to take account of variability in urine pH may explain some of the discrepancies observed when using MRs to compare enzyme activity across racial groups. For example, although strong correlations have been observed between enzyme activity assessed using different CYP2D6 probes in Caucasians 10,19–25 and Orientals, 24,26 consistency between the probes has been less in black Africans 22,24,25,27–31 and Arabs 32,33 . This may be explained partly by genetic variants of CYP2D6 that influence the relative docking of substrates at the active enzyme site 25 and that occur at different frequencies in different racial groups 24,34–39 .…”

Section: Discussionmentioning

confidence: 99%

Assessment of In Vivo CYP2D6 Activity: Differential Sensitivity of Commonly Used Probes to Urine pH

Özdemir

Crewe

Tucker

et al. 2004

The Journal of Clinical Pharma

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Drug/metabolite ratios (MRs) are used as in vivo markers of enzyme activity. The ratios are potentially confounded by the renal clearance of the drug (urine-based MRs) or metabolite (plasma-based MRs). The authors have investigated the relative sensitivity of urinary MR of 3 in vivo probe substrates of CYP2D6 debrisoquine (DB), dextromethorphan (DM), and metoprolol (MP) to changes in urine pH. Three groups of healthy volunteers each comprising 12 individuals were given DB (10 mg), DM (25 mg), or MP (100 mg) on 3 occasions. In 1 study arm, urine was acidified by the oral intake of ammonium chloride; in another, it was alkalinized by intake of sodium bicarbonate; and in the third, urine pH was uncontrolled. Urinary MP/alpha-hydroxy-MP, DM/dextrorphan, and DB/4-hydroxy-DB ratios were calculated. The mean(geo) MR for DB was not significantly different in any of the study arms, whereas those for MP and DM were significantly different under acidified and alkalinized urine conditions compared to uncontrolled urine pH (P < .01) and were correlated with urine pH (P < .001). Without control of urine pH, in vivo estimates of CYP2D6 metabolic activity are likely to be less precise using DM or MP as probe substrates compared to DB. Although this is unlikely to cause any problem in distinguishing the large functional differences in CYP2D6 in poor metabolizer (PM) and extensive metabolizer (EM) phenotypes, this may contribute to difficulties in differentiating in vivo metabolic activity among allelic variants within the overall CYP2D6 EM phenotype using MP or DM. However, because DB is not available in many countries (eg, United States), alternative in vivo markers of CYP2D6 with low sensitivity to urine pH should be sought.

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“…This dissociation between the log DMlDRP and log D/4-0H-D metabolic ratios observed in this group of Jordanian subjects has not been reported in other ethnic groups. The dissociation between log D/4-0H-D and log metoprolol/alpha-hydroxymetoprolol reported among Jordanians (22), Zambians (23) and Nigerians (24) has suggested that CYP2D6 might not be the only cytochrome P450 isoenzyme involved in the alpha-hydroxylation of metoprolol. Likewise, the dissociation of the log DMlDRP and log D/4-0H-D metabolic ratios reported in this study might also suggest that CYP2D6 is not the only isoenzyme involved in both the O-demethylation of dextromethorphan and the 4-hydroxylation of debrisoquine.…”

Section: Discussionmentioning

confidence: 99%

Dextromethorphan metabolism in Jordanians: Dissociation of dextromethorphan O-demethylation from debrisoquine 4-hydroxylation

Irshaid

Al-Hadidi

Latif

et al. 1996

European Journal of Drug Metabolism and Pharmacokinetics

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The concentrations of dextromethorphan (DM) and its metabolites dextrorphan (DRP), 3-methoxymorphinan (MM) and 3-hydroxymorphinan (HM) were measured in 8 h urine samples from 266 unrelated healthy Jordanian subjects following oral administration of 30 mg dextromethorphan hydrobromide and using a rapid, sensitive and precise HPLC method with fluorometric detection. The frequency of the 'poor' metabolizer status of DM-O-demethylation as judged by log DM/DRP was found to be 6.8% with a 95% confidence interval of 3.8-9.8%. There was a strong correlation between log DM/DRP and log total non-O-demethylated compounds (NODM)/total O-demethylated metabolites (ODM) metabolic ratios (r = 0.96, P < 0.01). However, one subject with log DM/DRP of 0.05 that classifies him as a poor metabolizer was found to have a log NODM/ODM of -0.73 which is in the range of extensive metabolizer status suggesting the presence of another cytochrome P450 isoenzyme involved in dextromethorphan O-demethylation. Dextromethorphan N-demethylation to 3-methoxymorphinan was detected in 55.3% of individuals. Furthermore, a dissociation between dextromethorphan O-demethylation and debrisoquine (D) 4-hydroxylation has been observed. Among the 116 subjects phenotyped with both dextromethorphan and debrisoquine, 7 were poor metabolizers of both, three were poor metabolizers of debrisoquine and extensive metabolizers of dextromethorphan whilst 4 were poor metabolizers of dextromethorphan and extensive metabolizers of debrisoquine, one of whom was reclassified as an extensive metabolizer of dextromethorphan using log NODM/ODM to characterize dextromethorphan metabolizer status.

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Metoprolol ?-hydroxylation is a poor probe for debrizoquine oxidation (CYP2D6) polymorphism in Jordanians

Cited by 11 publications

References 17 publications

Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N -acetyltransferase-2, and xanthine oxidase with the ″Cooperstown cocktail”

Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N -acetyltransferase-2, and xanthine oxidase with the ″Cooperstown cocktail”

Assessment of In Vivo CYP2D6 Activity: Differential Sensitivity of Commonly Used Probes to Urine pH

Dextromethorphan metabolism in Jordanians: Dissociation of dextromethorphan O-demethylation from debrisoquine 4-hydroxylation

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