Detection of an Endogenous Urinary Biomarker Associated With Cyp2D6 Activity Using Global Metabolomics

Tay-Sontheimer, Jessica; Shireman, Laura M.; Beyer, Richard P.; Senn, Taurence; Witten, Daniela; Pearce, Robin E.; Gaedigk, Andrea; Fomban, Cletus L Gana; Lutz, Justin D.; Isoherranen, Nina; Thummel, Kenneth E.; Fiehn, Oliver; Leeder, J. Steven; Lin, Yvonne S.

doi:10.2217/pgs.14.155

Cited by 37 publications

(41 citation statements)

References 50 publications

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“…We recently reported the detection and validation of M1, an unknown ion (mass-to-charge ratio of 444.3), that distinguished CYP2D6 poor metabolizers from other phenotypes in urine samples from 189 pediatric subjects (Tay-Sontheimer et al, 2014). Because M1 was absent in the urine of CYP2D6 poor metabolizers and present in the urine of all other CYP2D6 phenotypes, our data suggest that M1 may be a product of a reaction catalyzed by CYP2D6.…”

Section: Interindividual Variability In Cyp2d6-mediated Drugmentioning

confidence: 74%

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2015

Drug Metabolism and Disposition

144

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The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

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Section: Interindividual Variability In Cyp2d6-mediated Drugmentioning

confidence: 74%

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2015

Drug Metabolism and Disposition

144

View full text Add to dashboard Cite

show abstract

“…Therefore, the availability of endogenous biomarkers to assess transporter activities during early drug development would have substantial benefits for the pharmaceutical industry in order to avoid expensive clinical trials and also minimize the risk of late-stage failures and even drug withdrawal. In this regard, many attempts have been made to identify endogenous compounds that could reflect the activities of enzymes and transporters, such as CYP3A4 (Kanebratt et al, 2008;Diczfalusy et al, 2011;Shin et al, 2013;Kasichayanula et al, 2014), CYP2D6 (Tay-Sontheimer et al, 2014), MATEs (Ito et al, 2012;Kato et al, 2014;Müller et al, 2015), and OAT3 (Imamura et al, 2014) to improve prediction of DDI. However, as far as we know, no validated in vivo clinical endogenous probe of OATP1B has been identified.…”

Section: Introductionmentioning

confidence: 99%

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Shen

Dai

Liu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

109

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Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6-and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7-and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6-to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b 2/2 ), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1-to 18.4-fold; P , 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.

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“…The identification of endogenous metabolites for predicting individual drug PK characteristics (Huang et al 2015; Kienana et al 2016; Phapale et al 2010; Rahmioglu et al 2011; Shin et al 2013; Tay-Sontheimer et al 2014). …”

Section: Metabolomics and Pharmacometabolomicsmentioning

confidence: 99%

“…Much research efforts have focused on quantifying the influence of these changes on the PK, and to a lesser extent PD, of drugs in children. A recent study by Tay-Sontheimer et al (Tay-Sontheimer et al 2014), illustrated a first attempt to use pharmacometabolomic approaches to prospectively and non-invasively predict drug clearance of a CYP2D6 substrate in this population as well. Strong conclusions cannot yet be made based on this study, since parent and drug metabolite ratios were used to define enzyme activity.…”

Section: Pharmacometabolomics Informs Pharmacokineticsmentioning

confidence: 99%

Integration of pharmacometabolomics with pharmacokinetics and pharmacodynamics: towards personalized drug therapy

et al. 2016

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Personalized medicine, in modern drug therapy, aims at a tailored drug treatment accounting for inter-individual variations in drug pharmacology to treat individuals effectively and safely. The inter-individual variability in drug response upon drug administration is caused by the interplay between drug pharmacology and the patients’ (patho)physiological status. Individual variations in (patho)physiological status may result from genetic polymorphisms, environmental factors (including current/past treatments), demographic characteristics, and disease related factors. Identification and quantification of predictors of inter-individual variability in drug pharmacology is necessary to achieve personalized medicine. Here, we highlight the potential of pharmacometabolomics in prospectively informing on the inter-individual differences in drug pharmacology, including both pharmacokinetic (PK) and pharmacodynamic (PD) processes, and thereby guiding drug selection and drug dosing. This review focusses on the pharmacometabolomics studies that have additional value on top of the conventional covariates in predicting drug PK. Additionally, employing pharmacometabolomics to predict drug PD is highlighted, and we suggest not only considering the endogenous metabolites as static variables but to include also drug dose and temporal changes in drug concentration in these studies. Although there are many endogenous metabolite biomarkers identified to predict PK and more often to predict PD, validation of these biomarkers in terms of specificity, sensitivity, reproducibility and clinical relevance is highly important. Furthermore, the application of these identified biomarkers in routine clinical practice deserves notable attention to truly personalize drug treatment in the near future.

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Detection of an Endogenous Urinary Biomarker Associated With Cyp2D6 Activity Using Global Metabolomics

Cited by 37 publications

References 50 publications

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Integration of pharmacometabolomics with pharmacokinetics and pharmacodynamics: towards personalized drug therapy

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