Effects of UGT1A4 genetic polymorphisms on serum lamotrigine concentrations in Chinese children with epilepsy

Age‐ and Genotype‐Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate‐Glucuronosyltransferases in Human Liver

“…Uridine diphosphate‐glucuronosyltransferases (UGTs) are involved in the clearance (CL) of 10% of the top 200 prescribed drugs and constitute an important detoxification mechanism for diverse, potentially toxic xenobiotics such as polycyclic aromatic hydrocarbons, steroid hormones, nitrosamines, heterocyclic amines, fungal toxins, and aromatic amines . Importantly, drugs administered to children such as acetaminophen, valproic acid, lamotrigine, zidovudine, morphine, oxazepam, lorazepam, and furosemide are primarily metabolized by UGTs and have been shown to exhibit age‐dependent hepatic CL and pharmacokinetics (PKs). The plasma CL of morphine in neonates is significantly lower than in adults (4.7 ± 2.8 vs. 25.7 ± 4.7 ml min −1 kg −1 ) with >5‐fold lower metabolite (glucuronides)/parent ratios observed in neonates .…”

“…To fill this knowledge gap, we quantified four members of the UGT1A family (1A1, 1A4, 1A6, and 1A9) and two members of the UGT2B family (2B7 and 2B15) using a robust and selective liquid chromatography/tandem mass spectrometry (LC-MS/MS) proteomics approach, 15 in a panel of well-characterized (Table S1) microsomal samples isolated from human liver samples representing six age categories, neonatal (0-27 days), infancy (28-364 Figure 1 Protein content (pmol/mg microsomal protein) of the major UGT1As and UGT2Bs in human liver in different age categories. Age range for the corresponding categories (1)(2)(3)(4)(5)(6) are shown in the table. Abbreviations in the table indicate male (M), female (F) unknown (U), Asian (A), African American (AA), Caucasian (C), Hispanic (His), Native American (NA), and Pacific Islander (PI).…”

Pharmacokinetics of lamotrigine and its metabolite N‐2‐glucuronide: Influence of polymorphism of UDP‐glucuronosyltransferases and drug transporters

“…In another study the influence of UGT1A4 polymorphisms on LTG plasma concentration was investigated and a 52% decrease in the concentration of LTG was found in patients carrying the UGT1A4 142G > T (rs2011425) polymorphism compared with patients with wild‐type alleles . Similar findings on the effect of this polymorphism were also obtained in Chinese patients with epilepsy . On the other hand, a previous study showed no association of UGT1A4 142G > T polymorphism with LTG pharmacokinetics, whereas UGT2B7 –161C > T significantly influenced LTG oral clearance [19].…”

Interaction betweenABCG2 421C>Apolymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

“…In this respect, the present study has several limitations: first, it was based on morning trough concentrations as a part of routine TDM and not on a detailed pharmacokinetic evaluation. This, however, does not diminish its potential clinical relevance, since morning troughs are recommended indicators in TDM of AEDs ; next, certain treatment‐by‐variant allele carriage subsets were rather small – there were only six (2.9%) variant allele carriers at UGT1A4*2 70C>A , precluding any meaningful analysis; finally, some other potentially interesting polymorphisms such as UGT2B7 372A>G , and UGT1A4 –219C>T / 163G>A were not considered. The present results should be viewed within the scope of these limitations.…”

“…next, certain treatment-by-variant allele carriage subsets were rather smallthere were only six (2.9%) variant allele carriers at UGT1A4*2 70C>A, precluding any meaningful analysis; finally, some other potentially interesting polymorphisms such as UGT2B7 372A>G [12], and UGT1A4 -219C>T / 163G>A [35] were not considered. The present results should be viewed within the scope of these limitations.…”