Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs

The major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endog...

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Main Authors: K. Darney, L.S. Lautz, C. Béchaux, W. Wiecek, E. Testai, B. Amzal, J.L.C.M. Dorne
Format: Article
Language:English
Published: Elsevier 2021-11-01
Series:Environment International
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0160412021003858
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author K. Darney
L.S. Lautz
C. Béchaux
W. Wiecek
E. Testai
B. Amzal
J.L.C.M. Dorne
spellingShingle K. Darney
L.S. Lautz
C. Béchaux
W. Wiecek
E. Testai
B. Amzal
J.L.C.M. Dorne
Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs
Environment International
Human variability
CYP2D6
Pharmacokinetics
Bayesian inference
Meta-analysis
Risk assessment
author_facet K. Darney
L.S. Lautz
C. Béchaux
W. Wiecek
E. Testai
B. Amzal
J.L.C.M. Dorne
author_sort K. Darney
title Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs
title_short Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs
title_full Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs
title_fullStr Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs
title_full_unstemmed Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs
title_sort human variability in polymorphic cyp2d6 metabolism: implications for the risk assessment of chemicals in food and emerging designer drugs
publisher Elsevier
series Environment International
issn 0160-4120
publishDate 2021-11-01
description The major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endogenous compounds have been shown to be substrates of CYP2D6 including trace amines in the brain such as tyramine and 5-methoxytryptamine as well as anandamide and progesterone. Because of the polymorphic nature of CYP2D6, considerable inter-phenotypic and inter-ethnic differences in the pharmaco/toxicokinetics (PK/TK) and metabolism of CYP2D6 substrates exist with potential consequences on the pharmacology and toxicity of chemicals. Here, large extensive literature searches have been performed to collect PK data from published human studies for a wide range of pharmaceutical probe substrates and investigate human variability in CYP2D6 metabolism. The computed kinetic parameters resulted in the largest open source database, quantifying inter-phenotypic differences for the kinetics of CYP2D6 probe substrates in Caucasian and Asian populations, to date. The database is available in supplementary material (CYPD6 DB) and EFSA knowledge junction (DOI to added). Subsequently, meta-analyses using a hierarchical Bayesian model for markers of chronic oral exposure (oral clearance, area under the plasma concentration time curve) and acute oral exposure (maximum plasma concentration (Cmax) provided estimates of inter-phenotypic differences and CYP2D6-related uncertainty factors (UFs) for chemical risk assessment in Caucasian and Asian populations classified as ultra-rapid (UM), extensive (EMs), intermediate (IMs) and poor metabolisers (PMs). The model allowed the integration of inter-individual (i.e. inter-phenotypic and inter-ethnic), inter-compound and inter-study variability together with uncertainty in each PK parameter. Key findings include 1. Higher frequencies of PMs in Caucasian populations compared to Asian populations (>8% vs 1–2%) for which EM and IM were the most frequent phenotype. 2. Large inter-phenotypic differences in PK parameters for Caucasian EMs (coefficients of variation (CV) > 50%) compared with Caucasian PMs and Asian EMs and IMs (i.e CV < 40%). 3. Inter-phenotypic PK differences between EMs and PMs in Caucasian populations increase with the quantitative contribution of CYP2D6 for the metabolism (fm) for a range of substrates (fmCYP2D6 range: 20–95% of dose) (range: 1–54) to a much larger extent than those for Asian populations (range: 1–4). 4. Exponential meta-regressions between FmCYP2D6 in EMs and inter-phenotypic differences were also shown to differ between Caucasian and Asian populations as well as CYP2D6-related UFs. Finally, implications of these results for the risk assessment of food chemicals and emerging designer drugs of public health concern, as CYP2D6 substrates, are highlighted and include the integration of in vitro metabolism data and CYP2D6-variability distributions for the development of quantitative in vitro in vivo extrapolation models.
topic Human variability
CYP2D6
Pharmacokinetics
Bayesian inference
Meta-analysis
Risk assessment
url http://www.sciencedirect.com/science/article/pii/S0160412021003858
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spelling doaj-ecb47fe1c8c44e26badfe3c2aad580552021-08-18T04:21:14ZengElsevierEnvironment International0160-41202021-11-01156106760Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugsK. Darney0L.S. Lautz1C. Béchaux2W. Wiecek3E. Testai4B. Amzal5J.L.C.M. Dorne6French Agency for Food, Environmental and Occupational Health &amp; Safety (ANSES), 14 rue Pierre et Marie Curie, 94701 Maisons-Alfort, FranceFrench Agency for Food, Environmental and Occupational Health &amp; Safety (ANSES), 14 rue Pierre et Marie Curie, 94701 Maisons-Alfort, FranceFrench Agency for Food, Environmental and Occupational Health &amp; Safety (ANSES), 14 rue Pierre et Marie Curie, 94701 Maisons-Alfort, FranceCertara UK Ltd, Audrey House, 5th Floor, 16-20 Ely Place, London EC1N 6SN, United KingdomIstituto Superior di Sanità, Viale Regina Elena 299, 00161 Rome, ItalyQuinten Health, 75017 Paris, FranceEuropean Food Safety Authority, Via Carlo Magno,1A, 43126 Parma, Italy; Corresponding author.The major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endogenous compounds have been shown to be substrates of CYP2D6 including trace amines in the brain such as tyramine and 5-methoxytryptamine as well as anandamide and progesterone. Because of the polymorphic nature of CYP2D6, considerable inter-phenotypic and inter-ethnic differences in the pharmaco/toxicokinetics (PK/TK) and metabolism of CYP2D6 substrates exist with potential consequences on the pharmacology and toxicity of chemicals. Here, large extensive literature searches have been performed to collect PK data from published human studies for a wide range of pharmaceutical probe substrates and investigate human variability in CYP2D6 metabolism. The computed kinetic parameters resulted in the largest open source database, quantifying inter-phenotypic differences for the kinetics of CYP2D6 probe substrates in Caucasian and Asian populations, to date. The database is available in supplementary material (CYPD6 DB) and EFSA knowledge junction (DOI to added). Subsequently, meta-analyses using a hierarchical Bayesian model for markers of chronic oral exposure (oral clearance, area under the plasma concentration time curve) and acute oral exposure (maximum plasma concentration (Cmax) provided estimates of inter-phenotypic differences and CYP2D6-related uncertainty factors (UFs) for chemical risk assessment in Caucasian and Asian populations classified as ultra-rapid (UM), extensive (EMs), intermediate (IMs) and poor metabolisers (PMs). The model allowed the integration of inter-individual (i.e. inter-phenotypic and inter-ethnic), inter-compound and inter-study variability together with uncertainty in each PK parameter. Key findings include 1. Higher frequencies of PMs in Caucasian populations compared to Asian populations (>8% vs 1–2%) for which EM and IM were the most frequent phenotype. 2. Large inter-phenotypic differences in PK parameters for Caucasian EMs (coefficients of variation (CV) > 50%) compared with Caucasian PMs and Asian EMs and IMs (i.e CV < 40%). 3. Inter-phenotypic PK differences between EMs and PMs in Caucasian populations increase with the quantitative contribution of CYP2D6 for the metabolism (fm) for a range of substrates (fmCYP2D6 range: 20–95% of dose) (range: 1–54) to a much larger extent than those for Asian populations (range: 1–4). 4. Exponential meta-regressions between FmCYP2D6 in EMs and inter-phenotypic differences were also shown to differ between Caucasian and Asian populations as well as CYP2D6-related UFs. Finally, implications of these results for the risk assessment of food chemicals and emerging designer drugs of public health concern, as CYP2D6 substrates, are highlighted and include the integration of in vitro metabolism data and CYP2D6-variability distributions for the development of quantitative in vitro in vivo extrapolation models.http://www.sciencedirect.com/science/article/pii/S0160412021003858Human variabilityCYP2D6PharmacokineticsBayesian inferenceMeta-analysisRisk assessment