Insights into efficacy and safety of dapagliflozin treatment for the management in older adults with type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: This study aimed to evaluate the efficacy and safety of dapagliflozin as a monotherapy glucose-lowering drug treatment for older adults with diabetes. RESEARCH DESIGN & METHODS: Randomized controlled trial reports were retrieved from PubMed, Embase Cochrane Library, and Web of Science from database inception to 8 May 2021. Publication bias and heterogeneity were assessed using the Cochrane risk-of-bias tool and the Cochrane Q statistic, respectively. RESULTS: Compared with placebo, dapagliflozin as a monotherapy glucose-lowering drug did improve the control of glycosylated hemoglobin and fasting plasma glucose levels in older adults. Our analysis also confirmed that the body weight of older adults was well controlled under treatment of dapagliflozin as a monotherapy glucose-lowering drug. Patients in older adults with diabetes took a higher risk of genital infection and renal impairment or failure after treatment of dapagliflozin. In addition, treatment with dapagliflozin reduced the risk of hypoglycemia, and did not reveal increased risk of urinary tract infection and developing fractures compared to placebo in older adults. CONCLUSIONS: Dapagliflozin as a monotherapy glucose-lowering drug appeared to be an effective treatment for older adults with diabetes, although it might increase risk of genital infection and renal impairment or failure.

In vitro effects of opicapone on activity of human UDP-glucuronosyltransferases isoforms.

Catechol-O-methyltransferase (COMT) inhibitors are widely used as an add-on treatment to levodopa in adults with Parkinson's disease. It has been evidenced that the second-generation COMT inhibitors entacapone and tolcapone are potent inhibitors on human UDP-glucosyltransferases (UGTs), while the effect of the third-generation COMT inhibitor opicapone on human UGTs activities is unclear. The purpose of this study is to systemically investigate the effects of opicapone on human UGTs activities, and also to assess the potential risk of drug-drug interactions (DDIs) associated with opicapone. Our results indicated that opicapone is a broad-spectrum inhibitor of UGTs. Particularly, opicapone exhibited potent inhibition against UGT1A1, 1A7, 1A8, 1A9, and 1A10, with a range of inhibition constant Ki values of 1.31-10.58 µM. Furthermore, the DDI risk was quantitatively predicted by using the in vitro-in vivo extrapolation (IVIVE). The prediction suggested that co-administration of opicapone at 25 mg/day or 50 mg/day with drugs primarily cleared by hepatic UGT1A9 or intestinal UGT1A1, 1A7, 1A8, 1A9, or 1A10 might result in potential DDI via inhibition of intestinal or hepatic UGTs.

Prediction of Drug-Drug Interaction Between Dabrafenib and Irinotecan via UGT1A1-Mediated Glucuronidation.

BACKGROUND: Dabrafenib and irinotecan are two drugs that can be utilized to treat melanoma. A previous in vivo study has shown that dabrafenib enhances the antitumor activity of irinotecan in a xenograft model with unclear mechanism. OBJECTIVES: This study aims to investigate the inhibition of dabrafenib on SN-38 (the active metabolite of irinotecan) glucuronidation, trying to elucidate the possible mechanism underlying the synergistic effect and to provide a basis for further development and optimization of this combination in clinical research. METHODS: Recombinant human uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and human liver microsomes (HLMs) were employed to catalyze the glucuronidation of SN-38 in vitro. Inhibition kinetic analysis and quantitative prediction study were combined to predict drug-drug interaction (DDI) potential in vivo. RESULTS: Dabrafenib noncompetitively inhibited SN-38 glucuronidation in pooled HLMs and recombinant UGT1A1 with unbound inhibitor constant (Ki,u) values of 12.43 ± 0.28 and 3.89 ± 0.40 µM, respectively. Based on the in vitro Ki,u value and estimation of kinetic parameters, dabrafenib administered at 150 mg twice daily may result in about a 1-2% increase in the area under the curve (AUC) of SN-38 in vivo. However, the ratios of intra-enterocyte concentration of dabrafenib to Ki,u ([I]gut/Ki,u) are 2.73 and 8.72 in HLMs and recombinant UGT1A1, respectively, indicating a high risk of intestinal DDI when dabrafenib was used in combination with irinotecan. CONCLUSION: Dabrafenib is a potent noncompetitive inhibitor of UGT1A1 and may bring potential risk of DDI when combined with irinotecan.

Association between gene polymorphism and adverse effects in cancer patients receiving docetaxel treatment: a meta-analysis.

PURPOSE: Large interindividual variability in the pharmacokinetic properties of docetaxel has been reported, with the clearance of docetaxel varying nearly six fold, in which pharmacogenetics of docetaxel may play an essential role in addition to physiological factors. The association between the gene polymorphism and risk of adverse clinical effects in docetaxel treated patients has been examined in several studies, but their conclusions are, to some extent, controversial. To clarify the role of gene polymorphism in the clinical outcomes of docetaxel treatment, a meta-analysis was performed in the present study. METHODS: Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were employed to evaluate the impact of gene polymorphisms of CYP3A4, CYP3A5 and ABCB1. Four studies with 485 subjects were included in this study. Fixed or random-effects model was chosen according to heterogeneity to conduct the meta-analysis. Publication bias was evaluated by fail-safe numbers. RESULTS: Significant association was identified between the ABCB1 C3435T (rs1045642) polymorphism and risk of short-term recurrent hematological toxicity (TT vs. CC + TC OR = 2.91, 95% CI 1.30-6.52, P = 0.009; TT vs. CC OR = 4.23, 95% CI 1.69-10.57 P = 0.002). The association of the ABCB1 G2677T/A (rs2032582) polymorphism with risk of fluid retention was statistically significant (T(A)/T(A) vs. GG + GT(A) OR = 2.08, 95% CI 1.16-3.73, P = 0.01). No statistically significant association between the CYP3A5 A6986G (rs776746) polymorphism and adverse effects was observed in this study. Due to the limitations of included literature, we did not conduct meta-analysis on CYP3A4 gene polymorphism and adverse effects. CONCLUSION: An association between the ABCB1 C3435T (rs1045642), ABCB1 G2677T/A (rs2032582) polymorphism and risk of adverse effects of docetaxel was found by our meta-analysis. Namely, the TT homozygotes of the ABCB1 C3435T polymorphism may be associated with the risk of hematological toxicity. ABCB1 G2677T T(A)/T(A) genotype may be associated with the fluid retention. TRAIL REGISTRATION: PROSPERO 2020 CRD42020203132.

Withaferin A in the Treatment of Liver Diseases: Progress and Pharmacokinetic Insights.

Withaferin A (WA) is a natural steroidal compound used in Ayurvedic medicine in India and elsewhere. Although WA was used as an anticancer reagent for decades, its role in the treatment of liver diseases has only recently been experimentally explored. Here, the effects of WA in the treatment of liver injury, systematic inflammation, and liver cancer are reviewed, and the toxicity and metabolism of WA as well as pharmacological potentials of other extracts from Withania somnifera (W. somnifera) discussed. The pharmacokinetic behaviors of WA are summarized and pharmacokinetic insights into current progress and future opportunities are highlighted. SIGNIFICANCE STATEMENT: This review outlines the current experimental progress of Withaferin A (WA) hepatoprotective activities and highlights gaps in the field. This work also discusses the pharmacokinetics of WA that can be used to guide future studies for the possible treatment of liver diseases with this compound.

Inhibition of human UDP-glucuronosyltransferase enzyme by Dabrafenib: Implications for drug-drug interactions.

Dabrafenib is a novel small molecule tyrosine kinase inhibitor (TKI) which is used to treat metastatic melanoma. The aim of this research was to survey the effects of dabrafenib on human UDP-glucuronosyltransferases (UGTs) and to evaluate the risk of drug-drug interactions (DDIs). The formation rates for 4-methylumbelliferone (4-MU) glucuronide and trifluoperazine-glucuronide in 12 recombinant human UGT isoforms with or without dabrafenib were measured and HPLC was used to investigate the inhibitory effects of dabrafenib on UGTs. Inhibition kinetic studies were also conducted. In vitro-in vivo extrapolation approaches were further used to predict the risk of DDI potentials of dabrafenib via inhibition of UGTs. Our data indicated that dabrafenib had a broad inhibitory effect on 4-MU glucuronidation by inhibiting the activities of UGTs, especially on UGT1A1, UGT1A7, UGT1A8, and UGT1A9, and dabrafenib could increase the area under the curve of co-administered drugs. Dabrafenib is a strong inhibitor of several UGTs and the co-administration of dabrafenib with drugs primarily metabolized by UGT1A1, 1A7, 1A8 or 1A9 may induce potential DDIs.

Comparison of the drug-drug interactions potential of ibrutinib and acalabrutinib via inhibition of UDP-glucuronosyltransferase.

Ibrutinib and acalabrutinib are two Bruton's tyrosine kinase (BTK) inhibitors which have gained Food and Drug Administration (FDA) approval for the treatment of various B cell malignancies. Herein, we investigated the effects of the two drugs on UDP-glucuronosyltransferase (UGT) activities to evaluate their potential risk for drug-drug interactions (DDIs) via UGT inhibition. Our data indicated that ibrutinib exerted broad inhibition on most of UGTs, including a potent competitive inhibition against UGT1A1 with a Ki value of 0.90 ± 0.03 µM, a noncompetitive inhibition against UGT1A3 and UGT1A7 with Ki values of 0.88 ± 0.03 µM and 2.52 ± 0.23 µM, respectively, while acalabrutinib only exhibited weak UGT inhibition towards all tested UGT isoforms. DDI risk prediction suggested that the inhibition against UGT1A1 and UGT1A3 by ibrutinib might bring a potential DDIs risk, while acalabrutinib was unlikely to trigger clinically significant UGT-mediated DDIs due to its weak effects. Our study raises an alarm bell about potential DDI risk associated with ibrutinib, however, the extrapolation from in vitro data to in vivo drug interactions should be taken with caution, and additional systemic study is needed.