Common UGT1A9 polymorphisms do not have a clinically meaningful impact on the apparent oral clearance of dapagliflozin in type 2 diabetes mellitus.

Dapagliflozin is an inhibitor of human renal sodium-glucose cotransporter 2 (SGLT2), first approved for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin is primarily metabolized by uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9). The effect of UGT1A9 polymorphisms on dapagliflozin apparent oral clearance (CL/F) was studied with dapagliflozin population pharmacokinetic data and UGT1A9 genotype data (I.399C>T, rs2011404, rs6759892, rs7577677, rs4148323, UGT1A9*2 and UGT1A9*3) from a Phase 2 study conducted in subjects with T2DM (n = 187). An analysis of covariance (ANCOVA) model accounting for known covariates influencing dapagliflozin CL/F was applied to these data to quantify the impact of each UGT1A9 polymorphism relative to the wildtype UGT1A9 genotype. The analysis showed that the geometric mean ratios of dapagliflozin CL/F for all of the UGT1A9 polymorphisms studied were within the range of wildtype UGT1A9 CL/F values. Consequently, the polymorphisms of UGT1A9 studied had no clinically meaningful impact on the CL/F of dapagliflozin.

Meta-analysis of the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid.

PURPOSE: To investigate the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid (MPA). METHODS: PubMed, Web of Science, Embase, Cochrane Library, Wanfang Data, and the China Academic Journal Network Publishing Database were systematically searched for studies investigating the associations of IMPDH1, IMPDH2, and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking MPA. Associations were evaluated by pooled odds ratios (ORs) and effect sizes (ESs) with 95% confidence intervals (CIs). RESULTS: Twelve studies were included in the analysis, including a total of 2342 kidney transplant recipients. The results showed that compared with the TC + CC variant genotypes, the TT genotype of IMPDH2 3757 T > C was significantly associated with a higher risk of rejection (ES = 1.60, 95% CI = 1.07-2.40, P = 0.021), while there was no significant association of the IMPDH2 3757 T > C polymorphism with acute rejection within 1 year in kidney transplant recipients (OR = 1.49, 95% CI = 0.79-2.80, P = 0.217; ES = 1.44, 95% CI = 0.88-2.36, P = 0.142). The GG genotypes of IMPDH1 125G > A and IMPDH1 106G > A were significantly associated with a higher risk of rejection (ES = 1.91, 95% CI = 1.11-3.28, P = 0.019) and acute rejection within 1 year (ES = 2.12, 95% CI = 1.45-3.10, P < 0.001) than the variant genotypes GA + AA. The TT genotype of UGT1A9 275 T > A showed a decreased risk of rejection compared with the variant genotypes TA + AA (ES = 0.44, 95% CI = 0.23-0.84, P = 0.013). CONCLUSIONS: IMPDH1, IMPDH2, and UGT1A9 polymorphisms were associated with rejection in kidney transplant recipients, and the genetic backgrounds of patients should be considered when using MPA.

Regioselectivity significantly impacts microsomal glucuronidation efficiency of R/S-6, 7-, and 8-hydroxywarfarin.

Coumadin (R/S-warfarin) metabolism plays a critical role in patient response to anticoagulant therapy. Several cytochrome P450s oxidize warfarin into R/S-6-, 7-, 8-, 10, and 4'-hydroxywarfarin that can undergo subsequent glucuronidation by UDP-glucuronosyltransferases (UGTs); however, current studies on recombinant UGTs cannot be adequately extrapolated to microsomal glucuronidation capacities for the liver. Herein, we estimated the capacity of the average human liver to glucuronidate hydroxywarfarin and identified UGTs responsible for those metabolic reactions through inhibitor phenotyping. There was no observable activity toward R/S-warfarin, R/S-10-hydroxywarfarin or R/S-4'-hydroxywarfarin. The observed metabolic efficiencies (Vmax/Km) toward R/S-6-, 7-, and especially 8-hydroxywarfarin indicated a high glucuronidation capacity to metabolize these compounds. UGTs demonstrated strong regioselectivity toward the hydroxywarfarins. UGT1A6 and UGT1A1 played a major role in R/S-6- and 7-hydroxywarfarin glucuronidation, respectively, whereas UGT1A9 accounted for almost all of the generation of the R/S-8-hydroxywarfarin glucuronide. In summary, these studies expanded insights to glucuronidation of hydroxywarfarins by pooled human liver microsomes, novel roles for UGT1A6 and 1A9, and the overall degree of regioselectivity for the UGT reactions.

Identification of specific UGT1A9-mediated glucuronidation of licoricidin in human liver microsomes.

Licoricidin is a major prenylated isoflavone of Glycyrrhiza uralensis Fisch. (Leguminosae), and its pharmacological effects have been reported frequently. Typically, flavonoids having multiple hydroxyl groups are unambiguous substrates for glucuronyl conjugation by UDP-glucuronosyltransferases (UGTs). The pharmacological effects of flavonoids are derived from the conjugation of glucuronide to yield the bioactive metabolite. Here, the metabolism of licoricidin in pooled human liver microsomes (HLMs) was investigated using high-resolution quadrupole-orbitrap mass spectrometry. One metabolite (M1) was identified in HLMs after incubation with licoricidin in the presence of uridine 5'-diphosphoglucuronic acid (UDPGA) and NADPH. The structure of M1 was determined as a monoglucuronyl licoricidin, which was selectively produced by UGT1A9. Licoricidin showed a higher metabolic ratio and rapid metabolism with the recombinant human UGT1A9 than mycophenolic acid, a well-known UGT1A9 substrate. In conclusion, the selective formation of 7-glucuronyl licoricidin by UGT1A9 in HLMs could serve as a new selective substrate to determine the activity of UGT1A9 in vitro.

Inhibitory effects of sulfonylureas and non-steroidal anti-inflammatory drugs on in vitro metabolism of canagliflozin in human liver microsomes.

Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co-administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non-steroidal anti-inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of in vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs). Among sulfonylureas, glimepiride showed the most potent inhibitory effect against canagliflozin M7 metabolite formation, with an IC50 value of 88 µm, compared to chlorpropamide and gliclazide with IC50 values of more than 500 µm. Diclofenac inhibited M5 metabolite formation more than M7, with IC50 values of 32 µm for M5 and 80 µm for M7. Niflumic acid showed no inhibition activity against M5 formation, but had relatively selective inhibitory potency against M7 formation, which is catalysed by UGT1A9, with an IC50 value of 1.9 µm and an inhibition constant value of 0.8 µm. A clinical pharmacokinetic interaction between canagliflozin and sulfonylureas is unlikely. However, a possible clinically important drug interaction between niflumic acid and canagliflozin has been identified.

Impact of clinical factors and UGT1A9 and CYP2B6 genotype on inter-individual differences in propofol pharmacokinetics.

PURPOSE: Propofol is one of the most widely used fast-acting intravenously administered anesthetics. However, although large inter-individual differences in dose requirements and recovery time have been observed, there are few previous studies in which the association between several potential covariates, including genetic factors such as the UGT1A9 and CYP2B6 genotypes, and propofol pharmacokinetics was simultaneously examined. This study aimed to identify factors determining propofol pharmacokinetics. METHODS: Eighty-three patients were enrolled, and their blood samples were collected 1, 5, 10, and 15 min after administering a single intravenous bolus of propofol at a dose of 2.0 ml/kg to measure propofol plasma concentration. Area under the time-plasma concentration curve from zero up to the last measurable time point (AUC15min) was determined from the concentration data. The inter-individual variability of the propofol pharmacokinetics was evaluated by investigating relationships between AUC15min and genotype of UGT1A9 and CYP2B6; clinical factors, such as age, sex, body mass index (BMI), and preoperative hematological examination; and hemodynamic variables measured by a pulse dye densitogram analyzer. The Spearman rank correlation coefficient and the Mann-Whitney U test were used for the statistical analysis of continuous and categorical values, respectively. Subsequently, clinical factors that had p values of < 0.05 in the univariate analysis were examined in a multivariate analysis using multiple linear regression analysis. RESULTS: Age, BMI, indocyanine green disappearance ratio (K-ICG), hepatic blood flow (HBF), preoperative hemoglobin level, and sex were correlated with AUC15min (p < 0.05) in univariate analysis. Multivariate analysis performed to adjust for age, BMI, K-ICG, HBF, preoperative hemoglobin level, and sex revealed only BMI as an independent factor associated with AUC15min. CONCLUSIONS: This study demonstrated that BMI influences propofol pharmacokinetics after its administration as a single intravenous injection, while UGT1A9 and CYP2B6 SNPs, other clinical factors, and hemodynamic variables do not. These results suggest that BMI is an independent factor associated with propofol pharmacokinetics in several potential covariates. CLINICAL TRIALS REGISTRATION NUMBER: University Hospital Medical Information Network (UMIN000022948).

Effects of UGT1A9 genetic polymorphisms on monohydroxylated derivative of oxcarbazepine concentrations and oxcarbazepine monotherapeutic efficacy in Chinese patients with epilepsy.

AIM: The human UDP-glucuronosyltransferase which is genetically polymorphic catalyzes glucuronidations of various drugs. The interactions among UGT1A4, UGT1A6, UGT1A9, and UGT2B15 genetic polymorphisms, monohydroxylated derivative (MHD) of oxcarbazepine (OXC) plasma concentrations, and OXC monotherapeutic efficacy were explored in 124 Chinese patients with epilepsy receiving OXC monotherapy. METHOD: MHD is the major active metabolite of OXC, and its plasma concentration was measured using high-performance liquid chromatography when patients reached their maintenance dose of OXC. Genomic DNA was extracted from whole blood and SNP genotyping performed using PCR followed by dideoxy chain termination sequencing. We followed the patients for at least 1 year to evaluate the OXC monotherapy efficacy. Patients were divided into two groups according to their therapeutic outcome: group 1, seizure free; group 2, not seizure free. The data were analyzed using T test, one-way analysis of variance (ANOVA), Kruskal-Wallis test, chi-square test, Fisher's exact test, correlation analysis, and multivariate regression analysis. RESULT: T test analysis showed that MHD plasma concentrations were significantly different between the two groups (p = 0.002). One-way ANOVA followed by Bonferroni post hoc testing of four candidate SNPs revealed that carriers of the UGT1A9 variant allele I399 C > T (TT 13.28 ± 7.44 mg/L, TC 16.41 ± 6.53 mg/L) had significantly lower MHD plasma concentrations and poorer seizure control than noncarriers (CC 22.24 ± 8.49 mg/L, p < 0.05). CONCLUSION: In our study, we have demonstrated the effects of UGT1A9 genetic polymorphisms on MHD plasma concentrations and OXC therapeutic efficacy. Through MHD monitoring, we can predict OXC therapeutic efficacy, which may be useful for the personalization of OXC therapy in epileptic patients.

Scaling factors for the in vitro-in vivo extrapolation (IV-IVE) of renal drug and xenobiotic glucuronidation clearance.

AIM: To determine the scaling factors required for inclusion of renal drug glucuronidation clearance in the prediction of total clearance via glucuronidation (CLUGT ). METHODS: Microsomal protein per gram of kidney (MPPGK) was determined for human 'mixed' kidney (n = 5) microsomes (MKM). The glucuronidation activities of deferiprone (DEF), propofol (PRO) and zidovudine (AZT) by MKM and paired cortical (KCM) and medullary (KMM) microsomes were measured, along with the UGT 1A6, 1A9 and 2B7 protein contents of each enzyme source. Unbound intrinsic clearances (CLint,u,UGT ) for PRO and morphine (MOR; 3- and 6-) glucuronidation by MKM, human liver microsomes (HLM) and recombinant UGT1A9 and 2B7 were additionally determined. Data were scaled using in vitro-in vivo extrapolation (IV-IVE) approaches to assess the influence of renal CLint,u,UGT on the prediction accuracy of the calculated CLUGT values of PRO and MOR. RESULTS: MPPGK was 9.3 ± 2.0 mg g(-1) (mean ± SD). The respective rates of DEF (UGT1A6), PRO (UGT1A9) and AZT (UGT2B7) glucuronidation by KCM were 1.4-, 5.2- and 10.5-fold higher than those for KMM. UGT 1A6, 1A9 and 2B7 were the only enzymes expressed in kidney. Consistent with the activity data, the abundance of each of these enzymes was greater in KCM than in KMM. The abundance of UGT1A9 in MKM (61.3 pmol mg(-1) ) was 2.7 fold higher than that reported for HLM. CONCLUSIONS: Scaled renal PRO glucuronidation CLint,u,UGT was double that of liver. Renal CLint,u,UGT should be accounted for in the IV-IVE of UGT1A9 and considered for UGT1A6 and 2B7 substrates.

The Impact of Genetic Polymorphisms on the Anti-Hyperglycemic Effect of Dapagliflozin.

Background: The influence of genetic variants on the glucose-lowering effects of dapagliflozin remains unclear. This study aims to investigate the impact of polymorphisms in solute carrier family 5 member 2 (SLC5A2), uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9), solute carrier family 2 member 2 (SLC2A2) and member 4 (SLC2A4) on the anti-hyperglycemic effect of dapagliflozin in patients with type-2 diabetes mellitus (T2DM). Methods: A total of 141 patients with T2DM were included in this prospective cohort study. Twenty-nine single nucleotide polymorphisms (SNPs) were selected and genotyped using the Sequenom MassArray platform or Sanger sequencing. Glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels were compared before and after the treatment with dapagliflozin. Results: Among the 29 SNPs selected, 27 were successfully analyzed. After three months of dapagliflozin treatment, FBG levels were significantly reduced (8.00 mmol/L (5.45-10.71) mmol/L vs 6.40 mmol/L (5.45-9.20) mmol/L, p = 0.003) in patients with T2DM. However, there was no significant change in HbA1c levels (8.10% (6.88-10.00)% vs 8.10% (6.83-10.00)%, p = 0.452). Analysis of covariance showed that patients with the minor allele homozygote or heterozygote of rs12471030 (CT/TT), rs12988520 (AC/CC) or rs2602381 (TC/CC) had higher FBG levels compared to those with the major allele homozygote (p = 0.014, p = 0.024, and p = 0.044, respectively). After adjusting for baseline FBG level, age, gender, body mass index, use of insulin and use of metformin, three SNPs-rs12471030, rs12988520 and rs2602381-were associated with the anti-hyperglycemic effect of dapagliflozin. However, using a stringent significance threshold (p < 0.002 with Bonferroni correction), none of these selected SNPs were significantly associated with FBG and HbA1c levels after dapagliflozin treatment. Conclusion: After adjusting for confounding variables, polymorphisms in SLC5A2, UGT1A9, SLC2A2 and SLC2A4 genes were not associated with the anti-hyperglycemic effect of dapagliflozin in the Chinese population. Clinical Trial Registration Number: ChiCTR2200059645.

A high-affinity fluorescent probe for human uridine-disphosphate glucuronosyltransferase 1A9 function monitoring under environmental pollutant exposure.

Uridine-disphosphate glucuronosyltransferase 1A9 (UGT1A9), an important detoxification and inactivation enzyme for toxicants, regulates the exposure level of environmental pollutants in the human body and induces various toxicological consequences. However, an effective tool for high-throughput monitoring of UGT1A9 function under exposure to environmental pollutants is still lacking. In this study, 1,3-dichloro-7-hydroxy-9,9-dimethylacridin-2(9H)-one (DDAO) was found to exhibit excellent specificity and high affinity towards human UGT1A9. Remarkable changes in absorption and fluorescence signals after reacting with UGT1A9 were observed, due to the intramolecular charge transfer (ICT) mechanism. Importantly, DDAO was successfully applied to monitor the biological functions of UGT1A9 in response to environmental pollutant exposure not only in microsome samples, but also in living cells by using a high-throughput screening method. Meanwhile, the identified pollutants that disturb UGT1A9 functions were found to significantly influence the exposure level and retention time of bisphenol S/bisphenol A in living cells. Furthermore, the molecular mechanism underlying the inhibition of UGT1A9 by these pollutant-derived disruptors was elucidated by molecular docking and molecular dynamics simulations. Collectively, a fluorescent probe to characterize the responses of UGT1A9 towards environmental pollutants was developed, which was beneficial for elucidating the health hazards of environmental pollutants from a new perspective.

Teaching an Old Drug a New Trick: Targeting Treatment Resistance in Genitourinary Cancers.

In the quest for improving the clinical outcome of patients with metastatic genitourinary cancers, including metastatic renal cell carcinoma (mRCC), the emphasis often is on finding new targeted therapies. However, two studies by Jordan et al. (Oncogenesis 2020) and Wang et al. (Cancer Cell Int 2022) demonstrate the feasibility of improving the efficacy of a modestly effective drug Sorafenib against mRCC by attacking a mechanism hijacked by RCC cells for inactivating Sorafenib. The studies also identified hyaluronic acid synthase -3 (HAS3) as a bonafide target of Sorafenib in RCC cells. The studies demonstrate that an over-the-counter drug Hymecromone (4-methylumbelliferone) blocks inactivation of Sorafenib in RCC cells and improves its efficacy against mRCC through the inhibition of HAS3 expression and HA signaling. In the broader context, improving the efficacy of "old and failed drugs" that have favorable safety profiles should increase the availability of effective treatments for patients with advanced cancers.

The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus.

AIM(S): This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of dapagliflozin, a renal sodium glucose co-transporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus (T2DM). METHODS: A single 50 mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy non-diabetic subjects; patients with T2DM and normal kidney function and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance. Subsequently, 20 mg once daily multiple doses of dapagliflozin were evaluated in the patients with T2DM. Formation rates of dapagliflozin 3-O-glucuronide (D3OG), an inactive metabolite, were evaluated using human isolated kidney and liver microsomes. RESULTS: Plasma concentrations of dapagliflozin and D3OG were incrementally increased with declining kidney function. Steady-state Cmax for dapagliflozin were 4%, 6% and 9% higher and for D3OG were 20%, 37% and 52% higher in patients with mild, moderate and severe renal impairment, respectively, compared with normal function. AUC(0,τ) was likewise higher. D3OG formation in kidney microsomes was three-fold higher than in liver microsomes and 109-fold higher than in intestine microsomes. Compared with patients with normal renal function, pharmacodynamic effects were attenuated with renal impairment. Steady-state renal glucose clearance was reduced by 42%, 83% and 84% in patients with mild, moderate or severe renal impairment, respectively. CONCLUSIONS: These results indicate that both kidney and liver significantly contribute to dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. Dapagliflozin pharmacodynamics in diabetic subjects with moderate to severe renal impairment are consistent with the observation of reduced efficacy in this patient population.

Effect of polyethylene glycol 400 on the pharmacokinetics and tissue distribution of baicalin by intravenous injection based on the enzyme activity of UGT1A8/1A9.

Baicalin (BG) is a bioactive flavonoid extracted from the dried root of the medicinal plant, Scutellaria radix (SR) (dicotyledonous family, Labiatae), and has several biological activities. Polyethylene glycol 400 (PEG400) has been used as a suitable solvent for several traditional Chinese medicines (TCM) and is often used as an excipient for the compound preparation of SR. However, the drug-excipient interactions between BG and PEG400 are still unknown. Herein, we evaluated the effect of a single intravenous PEG400 administration on the BG levels of rats using pharmacokinetic and tissue distribution studies. A liver microsome and recombinant enzyme incubation system were used to further confirm the interaction mechanism between PEG400 and UDP-glucuronosyltransferases (UGTs) (UGT1A8 and UGT1A9). The pharmacokinetic study demonstrated that following the co-intravenous administration of PEG400 and BG, the total clearance (CLz) of BG in the rat plasma decreased by 101.60% (p < 0.05), whereas the area under the plasma concentration-time curve (AUC)0-t and AUC0-inf increased by 144.59% (p < 0.05) and 140.05% (p < 0.05), respectively. Additionally, the tissue distribution study showed that the concentration of BG and baicalein-6-O-ß-D-glucuronide (B6G) in the tissues increased, whereas baicalein (B) in the tissues decreased, and the total amount of BG and its metabolites in tissues altered following the intravenous administration of PEG400. We further found that PEG400 induced the UGT1A8 and UGT1A9 enzyme activities by affecting the maximum enzymatic velocity (Vmax) and Michaelis-Menten constant (Km) values of UGT1A8 and UGT1A9. In conclusion, our results demonstrated that PEG400 interaction with UGTs altered the pharmacokinetic behaviors and tissue distribution characteristics of BG and its metabolites in rats.

Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man.

Acetaminophen (paracetamol) is a widely used drug that causes adverse drug events that are often dose-dependent and related to plasma drug concentrations. Acetaminophen metabolism strongly depends on UGT1A enzymes. We aimed to investigate putative factors influencing acetaminophen pharmacokinetics. We analyzed acetaminophen pharmacokinetics after intravenous administration in 186 individuals, and we determined the effect of sex; body mass index (BMI); previous and concomitant therapy with UGT1A substrates, inhibitors, and inducers; as well as common variations in the genes coding for UGT1A1, UGT1A6, and UGT1A9. We identified sex and UGT1A6 genetic variants as major factors influencing acetaminophen pharmacokinetics, with women showing lower clearance (p < 0.001) and higher area under the plasma drug concentration-time curve (AUC) values than men (p < 0.001). UGT1A6 genetic variants were related to decreased acetaminophen biodisposition. Individuals who were homozygous or double-heterozygous for variant UGT1A6 alleles showed a 22.5% increase in t1/2 values and a 22.8 increase in drug exposure (p < 0.001, and 0.006, respectively) after correction by sex. The effect is related to the UGT1A6*2 and UGT1A6*4 variant alleles, whereas no effect of UGT1A6*3 and UGT1A9*3 alleles, BMI, or drug−drug interaction was identified in this study. We conclude that sex and UGT1A6 variants determine acetaminophen pharmacokinetics, thus providing evidence to eventually developing pharmacogenomics procedures and recommendations for acetaminophen use.

Cabozantinib Carries the Risk of Drug-Drug Interactions via Inhibition of UDPglucuronosyltransferase (UGT) 1A9.

BACKGROUND: Cabozantinib is a multiple receptor tyrosine kinases inhibitor (TKI) approved to treat progressive, metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma. Drugdrug interactions (DDIs) for cabozantinib have been identified involving the role of cytochromes P450. Although the previous study reported that cabozantinib showed a slight inhibition of UDP-glucuronosyltransferase (UGT) 1A1 at the highest concentration tested, there are no reports on the potential for UGTs-mediated-DDIs. Hence, the current study aims to address this knowledge gap. OBJECTIVE: This study aimed to investigate the inhibitory effect of cabozantinib on human UGTs and to quantitatively evaluate the DDI potential via UGT inhibition. METHODS: The inhibitory effects of cabozantinib on UGTs were determined by measuring the formation rates for 4- methylumbelliferone (4-MU) glucuronide and trifluoperazine N-glucuronide using recombinant human UGT isoforms in the absence or presence of cabozantinib. Inhibition kinetic studies were conducted to determine the type of inhibition of cabozantinib on UGTs and the corresponding inhibition constant (Ki) value. In vitro-in vivo extrapolation (IVIVE) was further employed to predict the potential risk of DDI in vivo. RESULTS: Cabozantinib displayed potent inhibition of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15. Cabozantinib exhibited noncompetitive inhibition towards UGT1A1 and 1A3 and inhibition towards UGT1A7 and 1A9. The Ki,u values (mean ± standard deviation) were calculated to be 2.15±0.11 µM, 0.83±0.05 µM, 0.75±0.04 µM and 0.18 ± 0.10 µM for UGT1A1, 1A3, 1A7 and 1A9, respectively. Co-administration of cabozantinib at the clinically approved dose of 60 mg/day or 140 mg/day may result in approximately a 26% to 60% increase in the systemic exposure of drugs predominantly cleared by UGT1A9, implying a high risk of DDIs. CONCLUSION: Cabozantinib has the potential to cause DDIs via the inhibition of UGT1A9; therefore, additional attention should be paid to the safety of the combined use of cabozantinib and drugs metabolized by UGT1A9.

A UPLC-MS/MS method reveals the pharmacokinetics and metabolism characteristics of kaempferol in rats under hypoxia.

As a natural flavonoid, kaempferol is widely distributed in natural medicines. Our study was aimed at analyzing and comparing the pharmacokinetic differences of kaempferol between normoxia and hypoxia in rats, to further explore the effect of hypoxia on drug metabolism enzymes. A sensitive UPLC-MS/MS method was established and validated for the determination of kaempferol in rat plasma. The results indicated that AUC, MRT, t1/2 and Cmax of kaempferol significantly increased and the clearance reduced in hypoxic rats. Based on the comparison of pharmacokinetics, the metabolites of kaempferol in hypoxic rats were identified by using UPLC-QTOF-MS and UNIFI 1.8 software. Then we explored the effect of hypoxia on the mRNA and protein expression of CYP1A2 and UGT1A9. The study revealed that hypoxia could markedly reduce the mRNA and protein expression of CYP1A2 and UGT1A9, resulting in the reduction of metabolic rate and enhancement of systematic exposure. Our data also indicated that we should pay attention to adjusting the dosage regimen and reducing drug interactions when drugs metabolized by CYP1A2 and UGT1A9 are used in combination with kaempferol. Our findings suggested the potential requirement for dose adjustment of kaempferol or its structural analogs in hypoxic condition.

GABRA1 and GABRB2 Polymorphisms are Associated with Propofol Susceptibility.

PURPOSE: To explore the effect of gene polymorphisms of propofol GABAA receptor and metabolic enzyme on drug susceptibility during the induction period of general anesthesia. PATIENTS AND METHODS: A total of 294 female patients aged 18-55 years, ASA I-II, who underwent hysteroscopy with intravenous general anesthesia, were included in the study. Anesthesia was induced by continuous intravenous infusion of propofol at 40 mg·kg-1·h-1. Infusion of propofol was ended when both the Modified Observer's Assessment of Awareness/Sedation scale (MOAA/S scale) decreased to 1 and the BIS index decreased to 60. The time when the MOAA/S scale decreased to 1 and the time when BIS index decreased to 60 was recorded to assess the susceptibility to the sedation effect. The maximum decreased percentage in mean arterial pressure (MAP) within 5 minutes was recorded to assess the susceptibility of cardiovascular response. Venous blood of each patient was collected to identify the presence of genetic variants in the GABRA1, GABRA2, GABRB2, GABRB3, GABRG2, CYP2B6, and UGT1A9 genes using the Sequenom MassARRAY® platform. RESULTS: After receiving propofol infusion, carriers of polymorphic GABRA1 rs4263535 G allele required significantly less time for BIS decreased to 60, while carriers of polymorphic GABRB2 rs3816596 T allele required significantly more time for BIS decreased to 60, carriers of polymorphic GABRA1 rs1157122 C allele and carriers of polymorphic GABRB2 rs76774144 T allele had a significantly less change in MAP. CONCLUSION: GABRB2 rs3816596 and GABRA1 rs4263535 polymorphisms are associated with susceptibility to the sedation effect of propofol. GABRA1 rs1157122 and GABRB2 rs76774144 polymorphisms are associated with the degree of drop in blood pressure after propofol infusion.

Transporter and metabolizer gene polymorphisms affect fluoroquinolone pharmacokinetic parameters.

Tuberculosis (TB) is an infectious disease that occurs globally. Treatment of TB has been hindered by problems with multidrug-resistant strains (MDR-TB). Fluoroquinolones are one of the main drugs used for the treatment of MDR-TB. The success of therapy can be influenced by genetic factors and their impact on pharmacokinetic parameters. This review was conducted by searching the PubMed database with keywords polymorphism and fluoroquinolones. The presence of gene polymorphisms, including UGT1A1, UGT1A9, SLCO1B1, and ABCB1, can affect fluoroquinolones pharmacokinetic parameters such as area under the curve (AUC), creatinine clearance (CCr), maximum plasma concentration (Cmax), half-life (t1/2) and peak time (tmax) of fluoroquinolones.

Polymorphisms of pharmacogenetic candidate genes affect etomidate anesthesia susceptibility.

Purpose: Etomidate is widely used in general anesthesia and sedation, and significant individual differences are observed during anesthesia induction. This study aimed to explore the molecular mechanisms of different etomidate susceptibility at the genetic level. Methods: 128 patients were enrolled in the study. The bispectral index (BIS), mean arterial pressure (MAP) and heart rate (HR) were recorded when the patients entered the operating room for 5 min, before the administration of etomidate, 30 s, 60 s, 90 s, 120 s and 150 s after the administration of etomidate, and the corresponding single nucleotide polymorphisms (SNPs) were analyzed. Results: Significant individual differences were observed in etomidate anesthesia. The results of two-way ANOVA showed that CYP2C9 rs1559, GABRB2 rs2561, GABRA2 rs279858, GABRA2 rs279863 were associated with the BIS value during etomidate anesthesia; UGT1A9 rs11692021 was associated with the Extended Observer's Assessment of Alertness and Sedation (EOAA/S) score during etomidate anesthesia; GABRB2 rs2561 was associated with MAP. Multiple linear stepwise regression model results showed that CYP2C9 rs1559, GABRA2 rs279858 and GABRB2 rs2561 were associated with the BIS value and UGT1A9 rs11692021 was associated with the EOAA/S score; GABRB2 rs2561 was associated with MAP. Conclusion: GABRA2 rs279858, GABRB2 rs2561, CYP2C9 rs1559 and UGT1A9 rs11692021 are the SNPs with individual differences during etomidate anesthesia. This is the first to study the SNPs of etomidate, which can provide certain evidence for the future use of etomidate anesthesia and theoretical basis for precision anesthesia.

The UGT1A9*22 genotype identifies a high-risk group for irinotecan toxicity among gastric cancer patients.

Several studies have shown associations between irinotecan toxicity and UGT1A genetic variations in colorectal and lung cancer, but only limited data are available for gastric cancer patients. We evaluated the frequencies of UGT1A polymorphisms and their relationship with clinicopathologic parameters in 382 Korean gastric cancer patients. Polymorphisms of UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*60, UGT1A7*2, UGT1A7*3, and UGT1A9*22 were genotyped by direct sequencing. In 98 patients treated with irinotecan-containing regimens, toxicity and response were compared according to the genotype. The UGT1A1*6 and UGT1A9*22 genotypes showed a higher prevalence in Korean gastric cancer patients, while the prevalence of the UG1A1*28 polymorphism was lower than in normal Koreans, as has been found in other studies of Asian populations. The incidence of severe diarrhea after irinotecan-containing treatment was more common in patients with the UGT1A1*6, UGT1A7*3, and UGT1A9*22 polymorphisms than in controls. The presence of the UGT1A1*6 allele also showed a significant association with grade III-IV neutropenia. Upon haplotype and diplotype analyses, almost every patient bearing the UGT1A1*6 or UGT1A7*3 variant also had the UGT1A9*22 polymorphism, and all severe manifestations of UGT1A polymorphism-associated toxicity were related to the UGT1A9*22 polymorphism. By genotyping UGT1A9*22 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A9*22 polymorphism, clinicians should closely monitor them for signs of severe toxicity such as intense diarrhea or neutropenia.