UGT1A1 Polymorphisms Research Articles

Study single nucleotide polymorphism in Promoter region of UGT1A1 Gene in Iraqi Patients with Gilbert's syndrome

This study aimed to detect genetic variants of the UGT1A1 gene in patients with Gilbert's syndrome. To detect this, primers were designed; PCR and direct sequencing were done for the promoter area of the gene as a diagnostic tool for the detection of any polymorphism. Variation and polymorphism were detected within the promoter mutants of the UDP glycosyltransferase _UGT1A1 gene that causes hyperbilirubinemia in a group of Iraqi patients compared with a group of the normal healthy individual as controls. The patients with hyperbilirubinemia in this study were 30 in which the total bilirubin level was more than 12 mg/dl serum; they included 25 males and 5 females, while the control group consisted of 20 healthy individuals. This study was carried out from September 2019 till April 2021. The result displayed high occurrence of Gilbert syndrome within male patients than in females, and regarding the analyses of mutation of bilirubin UDP glycosyltransferase _UGT1A1 gene, it is clear that the genotypic distribution of variation among the hyperbilirubinemia patients included all 30 patients, while SNP was detected in 18 patients out of 30 which indicate that the UGT1A1 gene mutation was a likely risk factor for the development of hyperbilirubinemia related Gilbert syndrome in Iraq. The homozygous and heterozygous polymorphisms A/G inside the promoter region of the UGT1A1 gene were effectively identified by sequencing. Our finding suggests that TA repeats and allele of UGT1A1 polymorphism A/G are associated with Gilbert's syndrome and act as genetic markers of this disease in Iraqi patients. To analyze data and sequence variation in gene, generous software was used after amplifying the gene. All processes include DNA extraction, PCR amplification, sequencing, and assembly.

Implementing Pre-Therapeutic UGT1A1 Genotyping in Clinical Practice: A Real-Life Study.

Current guidelines recommend pre-therapeutic UGT1A1 genotyping to guide irinotecan dosing, but the usefulness of this approach remains to be clarified. In 247 patients with advanced gastrointestinal cancers undergoing irinotecan-based chemotherapy, we prospectively performed UGT1A1*28 genotyping and we analyzed the incidence of severe neutropenia according to genotype-guided dose reductions. Overall, 28 (11.3%) and 92 (37.2%) patients were homozygous or heterozygous UGT1A1*28 carriers, respectively. Grade ≥ 3 neutropenia was reported in 39% of homozygous patients receiving an upfront dose reduction of irinotecan (median 40%, range 22–58%), in 20% of heterozygous or wild-type patients receiving full dose (ORvs*28/*28 genotype = 0.38; 95% CI: 0.14–1.03; p = 0.058), and in 15.3% of those receiving a reduced dose for clinical reasons (OR vs*28/*28 genotype = 0.28, 95% IC: 0.12–0.67; p = 0.004). Occurrence of severe neutropenia was inversely associated with dose reduction in UGT1A1*28 homozygous carriers (ORx10 unit = 0.62, 95% CI: 0.27–1.40, p = 0.249) and UGT1A1 heterozygous or wild-type patients (ORx10 unit = 0.87, 95% CI: 0.59–1.28, p = 0.478). Incidence of severe neutropenia was related to irinotecan doses and UGT1A1 polymorphisms. Upfront irinotecan dose reductions do not reduce the burden of grade ≥ 3 neutropenia in UGT1A1*28 homozygous carriers.

Safety and efficacy of combining genotype-guided irinotecan (Iri) with 5FU, leucovorin (LV), oxaliplatin (Ox), and docetaxel (Tax) (gFOLFOXIRITAX): The I-FLOAT phase 1 dose-escalation study for advanced upper GI cancers.

316 Background: 5FU, Ox, Iri, and Tax are each active in upper GI cancers. Triplet cytotoxic therapies (txs) improved survival compared to doublets/singlets. However, combination of all 4 agents (FOLFOXIRITAX) has not been studied. UGT1A1 polymorphisms reduce UGT enzymatic activity predisposing to Iri toxicity. We sought to determine the maximum tolerated dose (MTD) in the 1st month of tx among each of the low (L), intermediate (I) and high (H) risk UGT1A1 genotype (UGT) groups. Methods: Previously untx’d advanced upper GI cancer patients (pts) with ECOG PS 0/1 received gFOLFOXIRITAX (+ trastuzumab if HER2+) with pegfilgrastim. 5FU 2400mg/m2 over 46 hrs, LV 400mg/m2, Ox 85mg/m2, and Tax 25mg/m2 were given IV Q14 days. UGT-L, I, and H risk groups received starting Iri dose levels (DL1) of 120, 105 and 45mg/m2, respectively; Iri doses were escalated in each UGT group by 15mg/m2 increments and Tax to DL2 of 37.5mg/m2 using a I3+3 novel design (Liu & Ji. J Biopharm Stat 2020). Other endpoints included overall safety (thru up to 8 cycles before maintenance 5FU +/- Iri/tras), ORR (RECIST1.1), & ctDNA response (> 50% decrease in highest MAF) by G360 (Guardant Health). Results: From 6/30/2020-8/6/2021 20 pts (8F, 12M) enrolled: median age 50 (range 21-76); 8 ECOG PS 1, UGT-L:I:H with 3:14:3 pts; 10 esophageal, 6 gastric, 2 pancreatic, 1 unknown GI primary and 1 bile duct cancer; 2 pts HER2+; 18 metastatic, 2 locally advanced unresectable. The median (range) of albumin and neutrophil-to-lymphocyte ratio (NLR) were 3.9 mg/dL (3.3-4.6) and 4.28 (1.89-27.6), respectively; 80% (16/20) of pts had a NLR > 2.88, a poor prognostic marker. Dose limiting toxicities (DLTs) were seen in 4 pts: one G3 diarrhea (UGT-H, DL1/DL1 Iri/Tax), two G3 sepsis not neutropenic (one UGT-I, DL2/DL2 Iri/Tax; and one UGT-I, DL3/DL1 Iri/Tax) and one G3 fatigue (UGT-I DL2/DL2 Iri/Tax). MTD has not been reached in any UGT TAX DL1 cohorts to date; currently enrolling UGT-H Iri/Tax DL1/DL1, UGT-I DL4/DL1, & UGT-L DL3/DL1. Any Gr tx related toxicities in ³ 10% pts thru up to 8 cycles: nausea (70%), fatigue (70%, 5% G3), diarrhea (65%, 5% G3), anorexia (50%), peripheral neuropathy (30%, 5% G3), anemia (30%), thrombocytopenia (25%), elevated LFTs (25%), hyponatremia (25%), vomiting (20%), mucositis (20%, 5% G3), hyperglycemia (20%), edema (15%), alopecia (15%), hypocalcemia (15%) and dysgeusia (10%). Of evaluable pts across all cohorts, PR/CR was seen in 13/16 (81%) patients, with 2 (12.5%) SD and 1 (6.25%) PD for a disease control rate of 94%. Of evaluable pts, best ctDNA response was seen in 12/13 (92%). Conclusions: gFOLFOXIRITAX demonstrated tolerability at initial dose levels of Iri/Tax, with dose escalation continuing. Efficacy is promising and could be an aggressive approach in upper GI cancers having high relapse risk in curative-intent settings. Clinical trial information: NCT04361708.

Impact of MDR1 and UGT Gene Polymorphisms on Sodium Valproate Plasma Concentration in Patients with Epilepsy.

This study aimed to identify the effects of multidrug resistance gene 1 (MDR1) and UGT gene polymorphisms on the plasma concentration of VPA in subjects with epilepsy and provide a reference for individualized medicine of patients with epilepsy. One hundred subjects with epilepsy who were treated with sustained release VPA monotherapy were enrolled. Sanger sequencing was used to detect the genotypes of MDR1_G1199A, MDR1_G2677T/A, UGT1A6_A 552C, T19G and UGT2B7_C161T. By adjusting the plasma concentrations of VPA with body weight and a total daily dose of VPA, the concentration-to-dose ratio of VPA (CDRV) was obtained. Data were analyzed using SPSS17.0. No mutation of MDR1_G1199A gene was detected. MDR1_G2677T/A site T allele frequency is 43.5%, A is 14%. The genetic frequencies of UGT1A6_A552C, T19G, and UGT2B7_C161T were 29.5%, 25.5%, and 36%, respectively. Significant differences in CDRV were observed between carriers of TT, TG, and GG genotypes in the UGT1A6_T19G polymorphism (p = 0.021, p < 0.05). The CDRV was significantly lower in patients carry UGT1A6_T19G GG genotype compared to TG ((3.40 ± 1.61) μg.kg/mL.mg) and TT ((4.33 ± 1.97) μg.kg/mL.mg) genotype. While the MDR1_G2677T/A, UGT1A6_A552C and UGT2B7_C161T gene polymorphisms had no effect on the plasma concentration of VPA (p > 0.05). The genetic polymorphisms of UGT1A6_T19G significantly affect the plasma concentration of VPA in patients with epilepsy and the mutation of this locus can decrease the blood concentration of VPA. The MDR1_G2677T/A, UGT1A6_A552C and UGT2B7_C161T gene polymorphisms did not affect the plasma VPA concentration in Han patients with epilepsy.

All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide.

Irinotecan is an anticancer agent widely used for the treatment of solid tumors, including colorectal and pancreatic cancers. Severe neutropenia and diarrhea are common dose-limiting toxicities of irinotecan-based therapy, and UGT1A1 polymorphisms are one of the major risk factors of these toxicities. In 2005, the US Food and Drug Administration revised the drug label to indicate that patients with UGT1A1*28 homozygous genotype should receive a decreased dose of irinotecan. However, UGT1A1*28 testing is not routinely used in the clinic, and specific reasons include lack of access to concise information on this wide issue as well as mixed recommendations by regulatory and professional entities. To assist oncologists in assessing whether and when to use UGT1A1 genetic testing in patients receiving irinotecan-based therapies, this article provided (1) essential knowledge of UGT1A1 polymorphisms; (2) an update on the impact of UGT1A1 polymorphisms on efficacy and toxicity of contemporary irinotecan-based regimens; (3) dosing adjustments based upon the UGT1A1 genotypes, and (4) recommendations from currently available guidelines from the US and international scientific consortia and major oncology societies.

Correlation between nUGT1A1 gene polymorphisms and adverse events of irinotecan plus S-1 for patients with recurrent or metastatic esophageal squamous cell carcinoma: a prospective, open-label, randomized controlled trial (ESWN 01)

Objective: To investigate the correlation between UGT1A1 polymorphisms and the irinotecan plus S-1 regimen-induced toxicities in Chinese advanced esophageal squamous cell carcinoma (ESCC) patients. Methods: A total of 46 recurrent or metastatic ESCC patients selected from ESWN 01 trial were randomly assigned to irinotecan plus S-1 group [intravenous infusion of irinotecan (160 mg/m(2)) on day 1 and oral S-1 (80-120 mg) on days 1-10, repeated every 14 days]. Peripheral venous blood at baseline was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6 and UGT1A1*28 were analyzed by polymerase chain reaction (PCR) amplification. Irinotecan plus S-1 regimen-induced toxicities of patients with different UGT1A1 polymorphisms were observed. The correlation between UGT1A1 polymorphisms and the adverse effects was analyzed. Results: Among the 46 patients, the numbers of UGT1A1*6 wild type genotype (GG), mutant heterozygote (GA) and mutant homozygote (AA) were 30, 15 and 1, while those with UGT1A1*28 wild type genotype (TA6/6), mutant heterozygote (TA6/7) and mutant homozygote (TA7/7) were 36, 8 and 2, respectively. Only one patient with UGT1A1*6 AA genotype occurred grade 3 diarrhea, while one of the 2 patients with UGT1A1*28 TA7/7 genotype occurred grade 4 diarrhea. No neutropenia was observed in the patient with UGT1A1*6 AA genotype, however, both of the two patients with UGT1A1*28 TA7/7 genotype occurred grade 3-4 neutropenia. Patients with UGT1A1*28 genetic polymorphism (TA 6/7 or TA7/7) had a higher response rate compared with wild-type TA6/6 carriers. (55.6% versus 26.5%). Conclusions: The homozygous genotype of UGT1A1*6 AA and UGT1A1*28 TA7/7 are rare (<5%) in Chinese ESCC population. Not all homozygous AA and TA7/7 carriers occur severe dose limited toxicities (DLT) when treated with irinotecan (160 mg/m(2)) plus S-1 regimen for 2 weeks. However, it's still necessary torigorously observe the occurrence of severe diarrhea and neutropenia in patients with UGT1A1*6 AA and UGT1A1*28 TA7/7 and adjust the dose timely.

CYP2C19 & UGT1A6 genetic polymorphisms and the impact on Valproic acid-induced weight gain in people with epilepsy: Prospective genetic association study

ObjectivesTo study the association between CYP2C19*2 (681 G > A) and UGT1A6*2 (552A > C) polymorphisms on Valproic acid (VPA)-induced weight gain in People with epilepsy (PWE). MethodsWe recruited PWE on VPA monotherapy and genotyped for CYP2C19 and UGT1A6 polymorphisms. Association between CYP2C19 polymorphism and weight gain was the primary outcome parameter. We followed them up monthly for six months and recorded Body mass index (BMI), drug compliance, side effects, food frequency, physical activity. ResultsOf 108 participants recruited, we assessed the association between the polymorphism and weight gain in 101 PWE for CYP2C19*2 and 103 PWE for UGT1A6*2 polymorphism. The proportion of participants with weight gain was higher in those with poor and intermediate metabolizer genotypes of CYP2C19 (*1/*2 and *2/*2) compared to extensive metabolizers (*1/*1) [53.3 % vs 31.7 %, RR 1.68, 95 % CI (1.01–2.79), P = 0.03]. However, CYP2C19*2 allele did not show an increased risk of weight gain over the CYP2C19*1 allele. No association could be demonstrated with UGT1A6 genotypes and weight gain. In logistic regression analysis, CYP2C19*2 carrier genotype was the independent predictor of weight gain. OR 2.89 [95% CI (1.07–7.84)]. There were no significant association with serum TSH, fT4, testosterone, and valproate levels with CYP2C19 or UGT1A6 polymorphisms. SignificancePeople with epilepsy carrying CYP2C19 polymorphisms (*1/*2) and (*2/*2) had 3 times higher risk of VPA-induced weight gain compared to wild type (*1/*1).

Bilirubin Links HO-1 and UGT1A1*28 Gene Polymorphisms to Predict Cardiovascular Outcome in Patients Receiving Maintenance Hemodialysis.

Serum bilirubin levels, which are determined by a complex interplay of various enzymes, including heme oxygenase-1 (HO-1) and uridine diphosphate–glucuronosyl transferase (UGT1A1), may be protective against progression of cardiovascular disease (CVD) in hemodialysis patients. However, the combined effect of HO-1 and UGT1A1*28 gene polymorphisms on CVD outcomes among hemodialysis patients is still unknown. This retrospective study enrolled 1080 prevalent hemodialysis patients and the combined genetic polymorphisms of HO-1 and UGT1A1 on serum bilirubin were analyzed. Endpoints were CVD events and all-cause mortality. Mean serum bilirubin was highest in patients with S/S + S/L of the HO-1 promoter and UGT1A1 7/7 genotypes (Group 1), intermediate in those with S/S + S/L of the HO-1 promoter and UGT1A1 7/6 + 6/6 genotypes (Group 2), and lowest in the carriers with the L/L HO-1 promoter and UGT1A1 7/6 + 6/6 genotypes (Group 3) (p < 0.001). During a median follow-up of 50 months, 433 patients developed CVD. Compared with patients in Group 3, individuals among Groups 1 and 2 had significantly lower risks for CVD events (adjusted hazard ratios (aHRs) of 0.35 for Group 1 and 0.63 for Group 2), respectively. Compared with the lower bilirubin tertile, the aHRs were 0.72 for the middle tertile and 0.40 for the upper tertile for CVD events. We summarized that serum bilirubin as well as HO-1 and UGT1A1 gene polymorphisms were associated with CVD among patients receiving chronic hemodialysis.

Effects of UGT1A1 Polymorphism, Glucose-6-Phosphate Dehydrogenase Deficiency and Deletional (-3.7кb) α-Thalassemia Among Young Nigerians with Sickle Cell Anemia

Several genetic factors modulate the clinical course of sickle cell anemia (SCA), such as the βs-haplotypes, 3.7кb α-globin gene deletions (-α3.7), glucose-6-phosphate dehydrogenase deficiency (G6PD), UGT1A1 polymorphism and influencers of fetal hemoglobin production. While many studies on these modifiers have been conducted among patients in the developed world, little is known about how they impact SCA among Nigerians.We hypothesized that these factors could modulate SCA in the Nigerian population. Hence, we set out to determine whether βs-haplotype, -α3.7deletion, G6PD, and UGT1A1 polymorphism influence the laboratory markers and clinical events in young Nigerians with SCA.The study was conducted among 101 hydroxyurea-naïve SCA patients aged 2-21years, (median 9 years) in steady state, on regular follow up at the pediatric hematology unit of the Ekiti State University Teaching Hospital (EKSUTH), Ado Ekiti, Southwest Nigeria.Molecular analysis were conducted to confirm the diagnosis of SCA by polymerase chain reaction (PCR) and direct sequencing; alpha thalassemia by GAP-PCR; to determine UGT1A1 genotypes by Fragment Analysis; and BS haplotypes and G6PD genotypes by TaqMan SNP genotyping assay at the Hemocentro - University of Campinas, Brazil. Automated analysers were used to carry out hematologic and biochemical analyses. Records of the patients were examined for clinical events and steady state laboratory parameters. Serial abdominal ultrasounds were done as clinically indicated to diagnose gallstones. Institutional review board approval was obtained and the study protocols followed the Declaration of Helsinki as revised in 2000.Four (TA)n alleles (5, 6, 7, and 8) were found with gene frequencies of 0.11, 0.44, 0.40, and 0.05, respectively, grouped into 11 genotypes: TA5/5, 5/6, 5/7, 5/8, 6/5, 6/6, 6/7, 6/8, 7/7, 7/8, 8/8. Low Activity UGT1A1 genotypes (TA7/7, 7/8, 8/8) were found in 25 (24.7%). The Benin/Benin βs-haplotype was found in 94 (93%), Benin/Cameroun 4 (4%), Benin/Bantu 2 (2%), and Benin/Arab 1(1%). Mutation for the African variant of G6PD deficiency (202G>A) was found in 21(20.8%). None had the Mediterranean (563C>T) mutation. The frequency of 3.7 κb α-globin gene deletion was 34 (33.6%) αα /-α3.7 as heterozygous, 7 (7%) -α3.7/-α3.7 homozygous. Additionally, we found one (1%) α-globin triplication (αααanti3.7/αα).There was significant difference in bilirubin levels of the patients when differentiated by the UGT1A1 genotypes according to expected enzyme activity (low > intermediate > high activity with median unconjugated bilirubin levels of 1.8, 0.8, and 0.6mg/dL, respectively, P <0.0001). The presence of either alpha thalassemia or G6PD deficiency or both did not alter this trimodal pattern of bilirubin levels. Asymptomatic gallstone was found in 6 (5.9%) patients aged 10 to 16 years. Five of them had the low UGT1A1 activity genotypes 4 (TA7/7) & 1(TA7/8). The low genotype was significantly associated with gallstone when compared to other genotype groups 5/25 vs 1/76, P=0.0033. Bilirubin levels of patients with gallstone was significantly higher than age & sex matched subjects without gallstone (4.7 vs 1.2mg/dl, p=0.002) suggesting that the pathway to developing hyperbilirubinemia and gallstone is primarily driven by the influence of UGT1A1 genotype of our study cohorts.When we evaluated the influence of -α3.7 deletion, we found that participants with alpha thalassemia had higher frequencies of pain crisis in the preceding one year of the study with median episodes of 3 (range 0-6) vs 0 (range 0-6), P <0.0001. The presence of alpha thalassemia was significantly associated with decreased mean corpuscular volume, mean corpuscular hemoglobin, reticulocyte count and with a higher hemoglobin concentration (P <0.05) However, none of the 6 participants with leg ulcers had alpha thalassemia 0/ 42 vs 6/59 (P=0.039). There were no significant associations of βs-haplotypes and G6PD deficiency with both laboratory parameters and clinical events.In conclusion, our findings confirmed that both alpha thalassemia and UGT1A1 polymorphism influence the laboratory markers and clinical events of young Nigerians with SCA. It appears the influence of UGT1A1 polymorphism outweighs the modest ameliorating effect of alpha thalassemia on hyperbilirubinemia and cholelithogenesis among the patients. DisclosuresFertrin:Alexion Pharmaceuticals: Consultancy.

UGT1A1 Polymorphism and Mortality Outcome after Allogeneic Stem Cell Transplantation with Busulfan Based Regimen

Introduction: Mutations in the UGT1A1 gene have been implicated in Gilbert's syndrome, which shows mild hyperbilirubinemia, and a more aggressive childhood subtype, Crigler-Najjar syndrome. A common cause of decreased UGT1A1 activity is the insertion of a TA in the TATA box at the promoter region of the UGT1A1 gene which was named as UGT1A1*28 . Individuals with homozygous UGT1A1*28 had higher levels of serum bilirubin compared with those with heterozygous UGT1A1*28 or the wild-type allele.Gilbert's syndrome, also known as constitutional hepatic dysfunction or familial nonhemolytic jaundice, is an inherited disorder of the liver resulting in an overabundance of bilirubin. Most of the patients with Gilbert's syndrome are asymptomatic; however, they sometimes present with episodes of mild intermittent jaundice due to predominantly unconjugated hyperbilirubinemia.Emerging data on the role of genetic variants in the UGT1A1 gene confirm that the UGT1A1*28 allele is associated with severe toxicities in irinotecan-based chemotherapy.Busulfan is an alkylating drug with a narrow therapeutic index which can cause toxicity with higher plasma levels. Recently Mc Donald et al demonstrated in a large cohort of patients that overall mortality and non relapse mortality at 200d after hematopoietic stem cell transplantation were significantly higher in patients with Gilbert's syndrome receiving busulfan-containing conditioning regimens as compared to patients without Gilbert's syndrome without analysis of genomic variants affecting the function of UGT1A1.In a retrospective study we analyzed the role of UGT1A1*28 polymorphism on the transplant related mortality in a cohort of patients submitted to allogeneic stem cell transplantation conditioned with a busulfan-based regimen.Patients: We evaluated 74 patients (M/F 46/28), median age 48ys (range 21-66), underlying diseases were AML (50 pts), ALL (5 pts), MDS (10 pts), NHL (3 pts), CLL (1 pt), MPN (1 pt) and MM (2 pts). Conditioning regimen used were: BuCy (23 pts), BuFlu (32 pts), TBF (17 pts) and BuMel (2 pts).Results: We found 19 wild type (WT) pts (25%), 31 heterozygous (41%) and 24 homozygous pts (32%). Bilirubin levels were significantly higher in homozygous patients as compared to heterozygous and normal both at baseline and during the early follow-up post-transplant (p<0.001 and p=0.01 respectively) (Fig.1). When we looked at correlation between polymorphism and TRM at 200d and at 3ys after transplant it was 15.7% and 17.0% in WT pts, 6.4% and 26.6% in the heterozygous group and 20.8% and 27.3% in the homozygous group respectively (not statistically different).Conclusions: We demonstrated that patients homozygous for UGT1A1 polymorphism have higher levels of total bilirubin during transplant as compared to WT and heterozygotes but we did not find any correlation between TRM in patients receiving busulfan as part of the conditioning regimen for allo SCT and UGT1A1 polymorphism. Despite this result we are testing the polymorphism on a larger and homogenous cohort of patients because in our opinion it could be useful to identify patients with this genetic mutation responsible of high bilirubin levels at transplant which could be wrongly considered a criteria for diagnosis of VOD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Meta-Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure.

Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5′‐diphospho‐glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta‐analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration‐time curve (AUC) or maximum observed plasma concentration (Cmax) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9‐2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and Cmax increased in a dose‐proportional manner over the dose range of 0.5‐300 mg, and population‐predicted AUC and Cmax values for the 5‐ and 15‐mg ertugliflozin tablets administered in the fasted state demonstrated good agreement with the observed data. The largest change in ertugliflozin AUC was in subjects carrying the UGT1A9*3 heterozygous variant, with population‐predicted AUC (90% confidence interval) values of 485 ng·h/mL (458 to 510 ng·h/mL) and 1560 ng·h/mL (1480 to 1630 ng·h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng·h/mL (418 to 455 ng·h/mL) and 1410 ng·h/mL (1350 to 1480 ng·h/mL), respectively, in wild‐type subjects. Overall, the mean effects of the selected UGT1A9 variants on ertugliflozin AUC were within ±10% of the wild type. UGT1A9 genotype did not have any clinically meaningful effects on ertugliflozin exposure in healthy subjects. No ertugliflozin dose adjustment would be required in patients with the UGT1A9 variants assessed in this study.

Influence of UGT2B7 and UGT1A6 polymorphisms on plasma concentration to dose ratio of valproic acid in Chinese epileptic children

We explored the potential effects of genetic variations on the concentration to dose ratio (CDR) of valproic acid (VPA) in paediatric epilepsy patients. Two hundred and twenty-nine epileptic children on VPA monotherapy were included, and the VPA trough concentrations at steady-state of all subjects were determined. Nineteen single nucleotide polymorphisms (SNPs) of seven selected genes related to the metabolising enzymes and transporters of VPA were identified, and their influences on CDRVPA (a logarithmic transformation was performed if abnormally distributed) were evaluated. UGT2B7 rs7668258 (C>T) TT genotype was associated with a decrease in lnCDRVPA among epileptic children receiving VPA monotherapy (β=–0.191, p = 0.036). Significantly lower lnCDRVPA was also observed in paediatric patients with UGT1A6 rs2070959 (A>G) GG genotype compared to those AA genotype (β=–0.270, p = 0.021). This research indicated that UGT2B7 rs7668258 (C>T) and UGT1A6 rs2070959 (A>G) polymorphisms may be correlated to the normalised plasma concentrations of VPA in Chinese epileptic children. The associations could be abolished after Bonferroni's correction and our findings need to be validated in further and larger investigations.

CYP3A5 and UGT1A9 Polymorphisms Influence Immunosuppressive Therapy in Pediatric Kidney Transplant Recipients

Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on CYP3A5, MRP2 and UGT1A9 genes in Chilean pediatric kidney recipients using TAC and MPA. Patients and Methods: A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years [Q1–Q3 4.5–11.6 years] and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The CYP3A5 polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while MRP2 -24G > A, UGT1A9 -275T > A, and UGT1A9 -2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C0), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C0/D), and area under the curve in 12 h normalized by dose requirements (AUC0–12h/D). Results: The frequencies of the variant alleles CYP3A5*3, MRP2-24A, UGT1A9-275A, and UGT1A9-2152T were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC0–12h/TAC-D were 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1 carriers (CYP3A5*1/*3 and CYP3A5*1/*1). When analyzing patients with steroid withdrawal, CYP3A5*3/*3 patients had 1.7-fold higher AUC0–12h/TAC-D than the other genotypes. Patients carrying the CYP3A5*3/*3 genotype had higher TAC-C0, lower TAC-D and higher TAC-C0/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between MRP2 and UGT1A9 genotypes were observed in MPA-C0, MPA-D or MPA-C0/D. However, patients carrying the UGT1A9-275A allele had lower AUC0–12h/MPA-D than those carrying the UGT1A9-275T ancestral allele. Conclusions: These results support that CYP3A5 and UGT1A9 genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation.

Simple SummaryThe use of multi-gene testing platforms to individualize treatment is rapidly expanding into routine oncology practice. UGT1A1, which encodes for the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme, is commonly included on multi-gene molecular testing assays. UGT1A1 polymorphisms may influence drug-induced toxicities of numerous medications used in oncology. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is sparse and can differ depending on the referenced resource. We summarize the literature describing associations between UGT1A1 polymorphisms and toxicity risk with irinotecan, belinostat, pazopanib, and nilotinib. Resources that provide recommendations for UGT1A1-guided drug prescribing are reviewed, and considerations for implementation into patient care are provided.Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.

The Evaluation of Genetic Profiles of UGT1A4 and UGT1A6 in the Turkish Population

Aim: Uridine diphosphate glucuronosyltransferases (UGTs) are a superfamily of conjugation phase II enzymes and is responsible for catalyzing the glucuronidation of many endobiotic or xenobiotic substrates. The present study aimed to determine allele and genotype frequencies of UGT1A4 c.142T&gt;G, UGT1A6 c.541A&gt;G and UGT1A6 c.19T&gt;G polymorphisms in the healthy Turkish population and also to compare them with different population data. &#x0D; Material and Method: UGT1A4 c.142T&gt;G, UGT1A6 c.541A&gt;G and c.19T&gt;G polymorphisms were determined in DNA samples of 114 healthy Turkish volunteers using polymerase chain reaction and restriction fragment length polymorphism methods.&#x0D; Results: The frequencies of variant alleles were 12.7% for UGT1A4 c.142T&gt;G, 39.9% for UGT1A6 c.541A&gt;G and 44.7% for UGT1A6 c.19T&gt;G. The frequencies of the UGT1A4 and UGT1A6 variant alleles determined were observed to be similar to those of the majority of European populations. However, the UGT1A6 frequencies in the Turk population differed significantly from those reported specifically for the Thai and East Asian populations.&#x0D; Conclusion: This study introduces the frequencies of UGT1A4 and UGT1A6 polymorphisms in the Turkish population. To our knowledge, this is the first report that investigated the frequencies of UGT1A6 c.541A&gt;G and c.19T&gt;G polymorphisms in a healthy Turkish population. A study of the UGTA1A4*3 polymorphism was found in Turkish epilepsy patients in the literature search, but not in healthy individuals. Therefore, it can be stated that this study is also the first report investigating the UGT1A4*3 polymorphism in the healthy Turkish individuals. This study could ensure clinically beneficial information about drug metabolism by UGT1A4 and UGT1A6 in Turkish population.

Genetic Analysis of UGT1A1 Polymorphisms Using Preserved Dried Umbilical Cord for Assessing the Potential of Neonatal Jaundice as a Risk Factor for Autism Spectrum Disorder in Children.

Neonatal jaundice has been suggested as a perinatal risk factor for autism spectrum disorder (ASD). We examined UGT1A1 polymorphisms to assess the potential of neonatal jaundice as a risk factor for ASD in children by using DNA extracted from preserved umbilical cord. In total, 79 children with ASD were genotyped for UGT1A1*28 (c.-41-40dup), UGT1A1*6 (c.211 G > A), and UGT1A1*27 (c.686 C > A). The allele frequency of UGT1A1*6 (OR = 1.34, p = 0.26) and UGT1A1*28 (OR = 0.80, p = 0.54) and the prevalence of UGT1A1*28/*6 diplotypes did not differ significantly from those in the control population. No UGT1A1*27 allele was detected in the subjects. ASD symptom assessment scores were not associated with UGT1A1*28/*6/*27 genotypes or UGT1A1*28/*6 diplotypes. These results suggest that neonatal jaundice is not significantly associated with ASD.

UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI.

Background Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.

Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers.

The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5)metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. We analyzed 43 patients who received regorafenib 40-120mg/day; among them, 35 patients started at 120mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035). This study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.

Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms.

Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms. Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin. The area under the plasma concentration-time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity. In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

Influence of UGT1A1 promoter polymorphism, α-thalassemia and βs haplotype in bilirubin levels and cholelithiasis in a large sickle cell anemia cohort.

Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and βS haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and βS haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with βS haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.