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

Özdemir, Mahmut; Crewe, K; Tucker, Geoffrey T.; Rostami‐Hodjegan, Amin

doi:10.1177/0091270004269582

Cited by 29 publications

(27 citation statements)

References 58 publications

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“…Only *3, *4, *5, *6, *9, *10, *41 and *1ϫN CYP2D6 polymorphisms were investigated. Stamer et al recently documented that *45 and *46 CYP2D6 polymorphisms also contributed to the interindividual variability of enantiomer-specific tramadol metabolism in adults (19). Based on the overall low incidence of *45 and *46 polymorphism in whites (Ͻ2%), it is to be anticipated that the impact of these CYP2D6 polymorphisms is limited (22).…”

Section: Discussionmentioning

confidence: 99%

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

Allegaert¹,

Schaik

Vermeersch³

et al. 2008

Pediatr Res

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ABSTRACT:To document determinants of O-demethylation in critically ill (pre)term neonates and infants, tramadol (M) and O-demethyl tramadol (M1) concentrations were quantified in eightysix 24 h urine collections and 168 plasma samples. A significant correlation of urine log M/M1 (0.98, SD 0.66) and plasma log M/M1 (0.78, SD 0.45) with postmenstrual age (PMA) (r ϭ Ϫ0.69 and Ϫ0.65) was observed. One-way analysis of variance documented a significant decrease in urine log and plasma log M/M1 with increasing CYP2D6 activity score (F value 11.6 and 22.55). PMA and CYP2D6 activity score determined the urine and plasma log M/M1 (R 2 0.59 and 0.64) in a forward multiple regression model. We therefore conclude that PMA and CYP2D6 polymorphisms determined O-demethylation activity in (pre)term neonates and young infants, illustrating the impact of pharmacogenetics on drug metabolism in neonates although a relevant part of the interindividual varaibility remained unexplained. Besides compound-specific relevance, CYP2D6 iso-enzyme specific data on in vivo ontogeny of O-demethylation can contribute to safer and more effective administration of drugs metabolized by the same route in this population. I nterindividual variability in drug metabolism is based on constitution, environment, and genetics, but mainly reflects ontogeny in early life. Although the total cytochrome (CYP) content in fetal liver is 30 to 60% of adult content, iso-enzyme specific ontogeny precludes generalization of a single developmental pattern, necessitating iso-enzyme specific assessment (1). Based on observations on in vivo dextrometorphan in healthy infants and tramadol metabolism in critically ill (pre)term neonates and young infants, phenotypic activity of N-demethylation (CYP3A) displays slower increase to adult activity compared with O-demethylation (CYP2D6) (2,3). In addition to ontogeny, co-morbidity, co-medication, or polymorphisms in drug metabolizing enzymes and transporters likely further contribute to the interindividual variability of drug disposition (1,4,5).Tramadol (M) hydrochloride is a 4-phenyl-piperidine analogue of codeine and is a racemic mixture of two enantiomers. O-demethylation of (ϩ)-tramadol to O-(ϩ)-demethyl tramadol (M1) is catalyzed by CYP2D6 and to a much lesser extent, by CYP2B6. Tramadol therefore provide us with a probe drug to assess phenotypic variability in O-demethylation activity. The logarithmic value of tramadol over O-demethyl tramadol (log M/M1) has been used to study in vivo CYP2D6 activity in adults, children, and neonates (6 -9). Based on urine log M/M1 values, the impact of postmenstrual age (PMA) on phenotypic O-demethylation activity in 29 neonates and young infants was described, but PMA only in part explained (R adj Ϫ0.51) the interindividual variability in O-demethylation activity (8). The purpose of this study was to estimate the impact of ontogeny [PMA, postnatal age (PNA), weight] and pharmacogenetics (quantified by the CYP2D6 activity score) on interindividual variability of O-demethylation in earl...

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Section: Discussionmentioning

confidence: 99%

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

Allegaert¹,

Schaik

Vermeersch³

et al. 2008

Pediatr Res

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“…Although there was no such pronounced inhibition, propiverine effects on CYP1A2 were also evaluated, prompted by recent additional data (Walter et al, 2003). We also decided to evaluate the effects on CYP2D6, but these results will be reported separately because extensive additional evaluations are required to assess the validity of dextromethorphan metabolic ratios in urine and plasma for the quantification of drug-drug interactions (Streetman et al, 2000a;Ö zdemir et al, 2004;Borges et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers

Tomalik-Scharte

Jetter²,

Kinzig‐Schippers³

et al. 2005

Drug Metabolism and Disposition

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ABSTRACT:The present study was conducted to assess a possible in vivo effect of propiverine, an anticholinergic drug to treat urinary incontinence and related disorders, on the activity of intestinal CYP3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19, and CYP1A2. The activity of the respective cytochromes P450 was measured using the following metrics of selective substrates given as a tailored low-dose phenotyping cocktail: intestinal availability of midazolam Propiverine hydrochloride, described below as propiverine, is indicated for the treatment of urinary incontinence, as well as urinary urgency and frequency in patients who have either idiopathic detrusor overactivity (overactive bladder) or neurogenic detrusor overactivity (detrusor hyperreflexia) from spinal cord injuries, e.g., transverse lesion paraplegia. It exhibits antagonistic effects toward muscarinic acetylcholine receptors and calcium channel-modulating properties (Siegmund et al., 1990;Yono et al., 1999;Madersbacher and Mürtz, 2001).After oral administration, propiverine is rapidly and almost completely absorbed from the gastrointestinal tract. The maximal serum concentration is reached approximately 90 min after a single dose of 15 mg. Propiverine undergoes extensive presystemic metabolism via N-oxidation to propiverine-N-oxide with involvement of cytochrome P450 enzymes. Mean elimination half-life after chronic administration of propiverine is about 15 h. The major fraction of propiverine and its metabolites is eliminated in the urine (Haustein and Hüller, 1988;Siepmann et al., 1998). Information on the enzymes mediating phase I metabolism of propiverine has been obtained in several in vitro systems (APOGEPHA, data on file). The primary metabolic route involves the oxidation of the piperidyl-N and is mediated by CYP3A4 and flavin-containing monoxygenases 1 and 3, and leads to the formation of the much less active N-oxide. CYP2C9 and CYP2C19 may also mediate a fraction of overall propiverine elimination, whereas other enzymes (e.g., CYP1A2 and CYP2D6) were involved to a minor extent.Several studies concerning possible drug-drug interactions of propiverine have been published. Müller et al. (1993) demonstrated that there is no effect of the CYP2D6 genotype on propiverine biotransformation in humans, so that no effect of CYP2D6 inhibitors on propiverine pharmacokinetics is expected. Results of a study performed in rats provided no evidence for propiverine to cause relevant drug-drug interactions (Borchert et al., 1986). Studies on the effect of propiverine on drug-metabolizing enzymes in human and rat hepatocyte cultures demonstrated an increase in CYP3A4 mRNA and This study was supported by APOGEPHA Arzneimittel GmbH, Dresden, Germany.Article, publication date, and citation information can be found at

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“…With regard to the phenotyping protocol, the key issues are the choice of the analyte and the assay technique. Given the susceptibility of urinary metoprolol or dextromethorphan metabolic ratio to changes in urinary pH [121], alternative in vivo markers of CYP2D6 with low susceptibility to changes in urinary pH, such as point estimates from plasma concentrations or breath test, are to be highly preferred. Hu et al [122] have shown that the plasma sample at 2, 3, 4 or 5 h or the saliva sample at 6 h could be used for determining the DMR.…”

Section: Phenotyping Protocolsmentioning

confidence: 99%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

211

192

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Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. Pharmacogenetics and personalized medicineThe majority of drug-metabolizing enzymes (DMEs) are subject to genetic polymorphism and show some degree of functionally significant polymorphism in the population. The clearest data in this regard relate to cytochromes P450 CYP2D6 and CYP2C19 and thiopurine methyltransferase (TPMT). These genetically determined polymorphisms give rise to three distinct genotype-based subpopulations with respect to each DME, namely extensive metabolizers (EMs), poor metabolizers (PMs) and a subgroup in between, the intermediate metabolizers (IMs). In addition, for CYP2D6 and CYP2C19, there is a fourth genotype, the ultrarapid metabolizer (UM) genotype, resulting from inheritance of either multiple copies of the functional wild-type allele, such as CYP2D6*1, or a higher metabolic capacity resulting from increased transcription of DME due to the presence of a genetic variant found in the promoter ...

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

Cited by 29 publications

References 58 publications

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

Postmenstrual Age and CYP2D6 Polymorphisms Determine Tramadol O-demethylation in Critically Ill Neonates and Infants

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers

Addressing phenoconversion: the Achilles' heel of personalized medicine

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