Decreased capacity for debrisoquine metabolism among black Tanzanians

Wennerholm, Agneta; Johansson, Inger; Massele, Amos; Jande, Mary; Alm, Christina; Aden-Abdi, Y.; Dahl, Marja­‐Liisa; Ingelman‐Sundberg, Magnus; Bertilsson, Leif; Gustafsson, Lars L.

doi:10.1097/00008571-199912000-00005

Cited by 59 publications

(15 citation statements)

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“…Asians rarely have the PM phenotype, but within the EM population, they have lower levels of CYP2D6 activity compared to Caucasian EMs. The CYP2D6 * 10 allele is more frequent in Chinese, Japanese, and Korean populations compared to Whites and Blacks 32–37 . This allele has less active enzymatic activity compared to the wild‐type allele (* 1 ) 38 .…”

Section: Resultsmentioning

confidence: 99%

A Review and Assessment of Potential Sources of Ethnic Differences in Drug Responsiveness

Bjornsson¹,

Wagner

Donahue

et al. 2003

The Journal of Clinical Pharma

131

117

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The International Conference on Harmonization (ICH) E5 guidelines were developed to provide a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with the underlying objective to facilitate global drug development and registration. It is well recognized that all drugs exhibit significant inter-subject variability in pharmacokinetics and pharmacologic response and that such differences vary considerably among individual drugs and depend on a variety of factors. One such potential factor involves ethnicity. The objective of the present work was to perform an extensive review of the world literature on ethnic differences in drug disposition and responsiveness to determine their general significance in relation to drug development and registration. A few examples of suspected ethnic differences in pharmacokinetics or pharmacodynamics were identified. The available literature, however, was found to be heterologous, including a variety of study designs and research methodologies, and most of the publications were on drugs that were approved a long time ago.

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Section: Resultsmentioning

confidence: 99%

A Review and Assessment of Potential Sources of Ethnic Differences in Drug Responsiveness

Bjornsson¹,

Wagner

Donahue

et al. 2003

The Journal of Clinical Pharma

131

117

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“…The CYP2D6*3 and CYP2D6*4 alleles associated with the poor metabolizer phenotype were determined by allele‐specific polymerase chain reaction (PCR analysis) as described by Heim & Meyer (1990). The CYP2D6*6 was also determined by allele‐specific PCR as described by Wennerholm et al (1999). The CYP2D6*5 allele with deletion of the entire CYP2D6 gene was identified by long‐PCR analysis according to Wennerholm et al (1999).…”

Section: Methodsmentioning

confidence: 99%

“…The CYP2D6*6 was also determined by allele‐specific PCR as described by Wennerholm et al (1999). The CYP2D6*5 allele with deletion of the entire CYP2D6 gene was identified by long‐PCR analysis according to Wennerholm et al (1999). All samples were further analysed by long‐PCR for the duplicated/multiduplicated CYP2D6 gene (Lundqvist et al 1999).…”

Section: Methodsmentioning

confidence: 99%

Influence of CYP2C9, 2C19 and 2D6 Genetic Polymorphisms on the Steady‐State Plasma Concentrations of the Enantiomers of Fluoxetine and Norfluoxetine

Scordo

Spina

et al. 2005

Basic Clin Pharma Tox

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Abstract:The antidepressant fluoxetine is administered as racemic mixture of two enantiomers (S-and R-fluoxetine). While S-and R-fluoxetine are equipotent in blocking serotonin reuptake, the enantiomers of the demethylated metabolite, norfluoxetine, show marked differences in pharmacological activity, S-norfluoxetine being about 20 times as potent as Rnorfluoxetine as a serotonin reuptake inhibitor. In vitro and in vivo data suggest that the metabolism of fluoxetine to norfluoxetine is stereoselective and mediated, at least in part, by the polymorphic cytochrome P450 (CYP) isoenzymes CYP2D6, CYP2C9 and CYP2C19. In the present study, the influence of CYP2D6, CYP2C9 and CYP2C19 polymorphisms on the steady-state plasma concentrations of fluoxetine and norfluoxetine enantiomers was evaluated in 78 patients receiving chronic fluoxetine treatment (10-60 mg/day). The plasma concentrations of fluoxetine and norfluoxetine enantiomers were measured and CYP2D6, CYP2C9 and CYP2C19 genotypes were analyzed. No statistically significant relationship was identified between CYP2D6 or CYP2C19 genotypes and the dose normalised plasma concentrations of any of the enantiomers or the active moiety (i.e. the sum of S-fluoxetine, R-fluoxetine and S-norfluoxetine). However, the plasma concentration of S-norfluoxetine was very low in the only CYP2D6 poor metaboliser. Furthermore, the median S-norfluoxetine/S-fluoxetine ratios were higher in homozygous than in heterozygous extensive metabolisers (PϽ0.05). Among homozygous extensive metabolizers for CYP2D6, patients homozygous for CYP2C9*1 had lower dose-normalized Rfluoxetine concentrations and lower active moiety levels compared with those carrying detrimental CYP2C9 alleles (PϽ0.05). These results suggest that CYP2D6 and CYP2C9 polymorphisms contribute to the interindividual variability in fluoxetine pharmacokinetics at steady-state.Fluoxetine is one of the most widely prescribed selective serotonin reuptake inhibitors. Apart from its use in depression, it is also used for the treatment of a variety of other psychiatric and medical conditions, in which serotonin is thought to play a role (Gram 1994;Stokes & Holtz 1997). The commercially available drug is a racemic mixture of two enantiomers (S-and R-fluoxetine), which are approximately equipotent in blocking serotonin reuptake (Wong et al. 1985). Conversely, the enantiomers of the main demethylated metabolite, norfluoxetine, which are present in the circulation at higher concentrations than those of the parent drug, show marked differences in pharmacological activity, S-norfluoxetine being about 20 times more potent than R-norfluoxetine as a serotonin reuptake inhibitor both in vitro and in vivo (Fuller et al. 1992;Wong et al. 1993).

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“…The change from the hydrophilic Threonine to the hydrophobic Isoleucine at 107 position may explain the decreased enzyme activity. The frequency of CYP2D6*17 was found to be 34% in Zimbabweans [62], 17% in Tanzanians [63] and 28% in Ghanaians [64].…”

Section: Cyp 2d6mentioning

confidence: 93%

Pharmacokinetic and Pharmacodynamic Variability: A Daunting Challenge in Drug Therapy

Lin¹

2007

CDM

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Patients vary considerably in their response to drug therapy. A drug that proves to be pharmacologically effective in some patients at a given dose may be ineffective or even toxic in others. The interindividual variability in drug response represents a major challenge in drug therapy, particularly for drugs with narrow therapeutic index. The intensity and duration of a drug action are determined not only by pharmacokinetic processes, but also by pharmacodynamic processes. Therefore, the variability in drug response is a result of the variability in either pharmacokinetic or pharmacodynamic processes, or a combination of both. The purpose of this paper is to review the sources that contribute to pharmacokinetic and pharmacodynamic variability. Although the main focus will be on the genetic variability, the impact of environmental factors on drug response will also be discussed. Finally, the application and limitation of the concept of personalized medicine will be briefly discussed.

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Decreased capacity for debrisoquine metabolism among black Tanzanians

Cited by 59 publications

References 0 publications

A Review and Assessment of Potential Sources of Ethnic Differences in Drug Responsiveness

A Review and Assessment of Potential Sources of Ethnic Differences in Drug Responsiveness

Influence of CYP2C9, 2C19 and 2D6 Genetic Polymorphisms on the Steady‐State Plasma Concentrations of the Enantiomers of Fluoxetine and Norfluoxetine

Pharmacokinetic and Pharmacodynamic Variability: A Daunting Challenge in Drug Therapy

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