Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms
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TOXICOKINETICS AND METABOLISM
Human variability in isoform‑specific UDP‑glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors E. E. J. Kasteel1 · K. Darney2 · N. I. Kramer1 · J. L. C. M. Dorne3 · L. S. Lautz2 Received: 30 January 2020 / Accepted: 22 April 2020 © The Author(s) 2020
Abstract UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro–in vivo extrapolations in chemical risk assessment are discussed. Article Highlights • Extensive literature search of human kinetic parameters for UGT probe substrates. • Bayesian meta-analysis quantifying human variability in acute and chronic kinetic parameters. • UGT isoform-related uncertainty factors were below the 3.16 kinetic default uncertainty factor for most probe
substrates.
• Quantifying human variability in UGT polymorphisms.
Keywords Human variability · Pharmacokinetics · Uncertainty factor · UGT · Polymorphism
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02765-8) contains supplementary material, which is available to authorized users.
2
Risk Assessment Department, French Agency for Food, Environmental and Occupational Health and Safety (ANSES), 14 rue Pierre et Marie Curie, 94701 Maisons‑Alfort, France
3
European Food Safety Authority, Scientific Committee and Emerging Risks Unit, Via Carlo Magno 1A, 43126 Parma, Italy
* E. E. J. Kasteel [email protected] 1
Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, 3
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