Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

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.

Keywords: Human variability; Pharmacokinetics; Polymorphism; UGT; Uncertainty factor.

Fig. 1

Average distribution of the major UDP-glucuronosyltransferase isoforms in human liver (a), intestine (b) and kidney (c) (Lv et al. 2019)

Fig. 2

Human variability in the pharmacokinetics of isoform-specific UGT probe substrates, genetic polymorphisms and UGT-related uncertainty factors

Fig. 3

PRISMA diagram illustrating the extensive literature searches performed for the 13 isoform-specific UGT probe substrates (UGT1A and UGT2B subfamilies) and human pharmacokinetic studies

Fig. 4

Results of the meta-analyses reporting interindividual differences in non-phenotyped healthy adults for 14 isoform-specific UGT probe substrates. Data are expressed as log geometric means (GM) for markers of acute (Cmax) and chronic (AUC, clearance) exposure. AUC (normalised to dose, a), clearance (normalised to body weight, b), and Cmax (normalised to dose, c). Open squares: oral exposure; solid circles: IV exposure. Red data points: healthy volunteers; blue data points: patients. 21d: repeated dose for 21 days

Fig. 5

Inter-individual differences in markers of chronic exposure (area under the concentration–time curve (AUC)) for isoform-specific UGT probe substrates across world populations of different geographical ancestry. For each UGT isoform included in the study, one probe substrate is shown. Graphs for other probe substrates and other PK parameters are accessible in Supplementary Material 3

Fig. 6

Frequencies of single nucleotide polymorphisms (SNPs) genotypes for UGT1A1*28 (a), UGT1A3 (b), UGT1A4*2 (C70A) (c) UGT1A4*3 (T142G) (d), UGT1A6*2 (e), UGT1A9*22 (f), UGT2B7 (C802T) (g), and UGT2B15*2 (h) in human populations of different geographical ancestries. C(E) central, N north, S south, E east, SE southeast