-
Scientific Reports Apr 2017Despite the therapeutic success of tenofovir (TFV) for treatment of HIV-1 infection, numerous cases of nephrotoxicity have been reported. Mitochondrial toxicity has been...
Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity.
Despite the therapeutic success of tenofovir (TFV) for treatment of HIV-1 infection, numerous cases of nephrotoxicity have been reported. Mitochondrial toxicity has been purported as the major target of TFV-associated renal tubulopathy but the underlying molecular mechanism remains unclear. In this report, we use metabolomics and proteomics with HK-2 cells and animal models to dissect the molecular pathways underlying nephropathy caused by TFV and its more toxic analog, adefovir (ADV). Proteomic analysis shows that mitochondrial chaperone TRAP1 and mtDNA replicating protein SSBP1 were significantly down-regulated in TFV and ADV treated HK-2 cells compared with controls. Transmission electron microscopy (TEM) revealed that TFV and ADV-treated HK-2 cells had accumulated glycogen, a phenotype that was also observed in mice treated with TFV and ADV. Analysis of the proteins in TCA cycle showed succinate dehydrogenase subunit B (SDHB) was nearly depleted in glucose oxidative phosphorylation pathway however certain enzymes in the glycolysis and glycogen synthesis pathway had elevated expression in TFV and ADV-treated HK-2 cells. These results suggest that TFV and ADV may cause mitochondrial dysfunction in renal tubular cells and reprogramming of glucose metabolism. The resulting glycogen accumulation may partially contribute to TFV and ADV induced renal dysfunction.
Topics: Adenine; Animals; Anti-HIV Agents; Cell Line; Cell Proliferation; Cell Survival; Glucose; Glycolysis; HSP90 Heat-Shock Proteins; Humans; Kidney Diseases; Mice; Mitochondria; Models, Biological; Organophosphonates; Proteome; Proteomics; Succinate Dehydrogenase; Tenofovir
PubMed: 28397817
DOI: 10.1038/srep46344 -
Biochemical Pharmacology Sep 2016Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of...
BACKGROUND AND AIMS
Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of glomerular filtration with active tubular transport. Nonalcoholic steatohepatitis is a variable in drug disposition, yet the impact on renal transport processes has yet to be fully understood. The goal of this study was to determine the effect of nonalcoholic steatohepatitis on the pharmacokinetics of adefovir in rats given a control or methionine and choline deficient diet to induce nonalcoholic steatohepatitis.
METHODS
Animals received a bolus dose of 7mg/kg (35μCi/kg) [(3)H] adefovir with consequent measurement of plasma and urine concentrations. Inulin clearance was used to determine glomerular filtration rate.
RESULTS
Methionine and choline deficient diet-induced nonalcoholic steatohepatitis prolonged the elimination half-life of adefovir. This observation occurred in conjunction with reduced distribution volume and hepatic levels of adefovir. Notably, despite these changes, renal clearance and overall clearance were not changed, despite markedly reduced glomerular filtration rate in nonalcoholic steatohepatitis. Alteration of glomerular filtration rate was fully compensated for by a significant increase in tubular secretion of adefovir. Analysis of renal transporters confirmed transcriptional up-regulation of Mrp4, the major transporter for adefovir tubular secretion.
CONCLUSIONS
This study demonstrates changes to glomerular filtration and tubular secretion that alter pharmacokinetics of adefovir in nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis-induced changes in renal drug elimination processes could have major implications in variable drug response and the potential for toxicity.
Topics: Adenine; Animals; Choline; Diet; Glomerular Filtration Rate; Kidney; Male; Methionine; Non-alcoholic Fatty Liver Disease; Organophosphonates; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Inhibitors
PubMed: 27381944
DOI: 10.1016/j.bcp.2016.07.001 -
Biological & Pharmaceutical Bulletin 2015The aim of this study was to investigate the effect of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), an active form of vitamin D, on the oral absorption and disposition of...
The aim of this study was to investigate the effect of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), an active form of vitamin D, on the oral absorption and disposition of adefovir dipivoxil (P-glycoprotein (P-gp) substrate) and its major active metabolite, adefovir (multidrug resistance-associated protein 4 (Mrp4) substrate), in rats. The pharmacokinetics of intravenous adefovir and oral adefovir dipivoxil was evaluated in control and 1,25(OH)2D3-treated rats. The intestinal absorption of adefovir dipivoxil was investigated through an in situ closed loop study, and the tissue distribution of adefovir after oral administration of adefovir dipivoxil was evaluated in the two groups. There was no significant difference in pharmacokinetic parameters of intravenous adefovir between the two groups. Importantly, the total area under the plasma concentration-time curve from time zero to time infinity (AUC), peak plasma concentration (Cmax) and extent of absolute oral bioavailability (F) of adefovir after oral administration of adefovir dipivoxil were significantly higher in 1,25(OH)2D3-treated rats than in control rats. In the in situ closed loop study, there was no significant difference in the remaining fraction of adefovir dipivoxil in the duodenum, jejunum and ileum loops between the two groups. In the tissue distribution study after oral administration of adefovir dipivoxil, the tissue-to-plasma partition coefficients of adefovir in the liver, brain, kidney, and intestine were significantly lower in the 1,25(OH)2D3-treated rats than in control rats. The present study indicates that 1,25(OH)2D3 treatment can enhance the oral absorption of adefovir dipivoxil, likely via the induction of basolateral Mrp4 function in rat intestine. However, the impact of 1,25(OH)2D3 treatment on the pharmacokinetics of intravenous adefovir was limited. These results could lead to further studies in clinically significant P-gp and/or MRP4-mediated 1,25(OH)2D3-drug interactions.
Topics: Adenine; Administration, Oral; Animals; Area Under Curve; Biological Availability; Calcitriol; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Multidrug Resistance-Associated Proteins; Organophosphonates; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 26521823
DOI: 10.1248/bpb.b15-00356 -
Gut and Liver Mar 2017The primary goal of therapy for chronic hepatitis B (CHB) is to prevent liver disease progression. Hepatitis B surface antigen (HBsAg) seroclearance or seroconversion is... (Review)
Review
The primary goal of therapy for chronic hepatitis B (CHB) is to prevent liver disease progression. Hepatitis B surface antigen (HBsAg) seroclearance or seroconversion is regarded as an optimal endpoint to discontinue treatment. However, HBsAg seroclearance occurs very rarely with nucleos(t)ide analog (NUC) treatment, and long-term, almost indefinite, NUC treatment is required for the majority of patients. In patients with drug-resistant hepatitis B virus (HBV), a combination of tenofovir disoproxil fumarate (TDF) and entecavir (ETV), which is currently regarded as the strongest combination therapy against HBV, would be potentially safe to prevent the emergence of additional HBV resistance mutations. However, long-term tolerance data are lacking, and cost may be an issue for combination therapies. Several recent, well-designed, randomized controlled trials have shown that TDF monotherapy provides similar antiviral efficacy compared with the combination of TDF and ETV. Furthermore, no additional HBV resistance mutations emerged during TDF monotherapy for up to 96 weeks. Considering a comparable antiviral efficacy, extremely low risk of TDF-resistance, lower cost, and better safety potential, TDF monotherapy would be a reasonable choice for the treatment of drug-resistant patients with CHB.
Topics: Adenine; Antiviral Agents; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Tenofovir
PubMed: 28183162
DOI: 10.5009/gnl15562 -
Advances in Therapy Apr 2016A comprehensive and up-to-date network meta-analysis (NMA) helps to determine the comparative efficacies of nucleos(t)ide analogs (NAs) in patients with chronic... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
A comprehensive and up-to-date network meta-analysis (NMA) helps to determine the comparative efficacies of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B (CHB). The aim of this NMA was to assess the efficacy of telbivudine versus adefovir, entecavir, lamivudine, and tenofovir in nucleos(t)ide-naïve hepatitis B e antigen (HBeAg)-positive patients with CHB.
METHODS
A systematic review was conducted to search Medline, Medline-In Process, EMBASE, and the Cochrane Central Register of Controlled Trials databases for publications of randomized controlled trials (RCTs). NMA was performed to compare the efficacy outcomes of telbivudine versus other approved NAs at 1- and 2-year time points.
RESULTS
A total of 75 RCTs were included in the systematic review. At the 1-year time point, telbivudine was associated with significantly higher rates of: (1) HBeAg seroconversion than adefovir [odds ratio (OR) 1.99 (95% credible interval (CrI): 1.05, 3.45)], entecavir [OR 2.00 (95% CrI: 1.44, 2.82)] and lamivudine [OR 1.49 (95% CrI: 1.10, 2.03)]; (2) HBeAg loss than entecavir [OR 1.85 (95% CrI: 1.28, 2.76)] and lamivudine [OR 1.62 (95% CrI: 1.20, 2.24)]; (3) alanine aminotransferase (ALT) normalization than lamivudine [OR 1.50 (95% CrI: 1.05, 2.21)]; and (4) hepatitis B virus (HBV) DNA suppression than adefovir [OR 2.77 (95% CrI: 1.28, 5.45)] and lamivudine [OR 2.97 (95% CrI: 1.99, 4.53)]. At the 2-year time point, the relative efficacy outcomes were not statistically significant.
CONCLUSION
At 1 year, telbivudine was superior to adefovir, entecavir and lamivudine in HBeAg seroconversion, and to entecavir and lamivudine in HBeAg loss. Telbivudine was also superior to lamivudine in ALT normalization and to adefovir and lamivudine in suppressing HBV DNA levels.
FUNDING
Novartis Pharma AG.
Topics: Antiviral Agents; Comparative Effectiveness Research; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Nucleic Acid Synthesis Inhibitors; Randomized Controlled Trials as Topic; Seroconversion; Telbivudine; Thymidine; Time; Treatment Outcome
PubMed: 26921204
DOI: 10.1007/s12325-016-0305-x -
PloS One 2018Hepatitis B virus (HBV) infection is a liver disorder that can result in cirrhosis, liver failure and hepatocellular carcinoma. HBV infection remains a major global...
Hepatitis B virus (HBV) infection is a liver disorder that can result in cirrhosis, liver failure and hepatocellular carcinoma. HBV infection remains a major global health problem, as it affects more 350 million people chronically and kills roughly 600,000 people annually. Drugs currently used against HBV include IFN-α that decreases viremia, inflammation and the growth of liver fibrosis, and adefovir that decreases the viral load. Each of these drugs can have severe side-effects. In the present paper, we consider the treatment of chronic HBV by a combination of IFN-α and adefovir, and raise the following question: What should be the optimal ratio between IFN-α and adefovir in order to achieve the best 'efficacy' under constraints on the total amount of the drugs; here the efficacy is measured by the reduction of the levels of inflammation and of fibrosis? We develop a mathematical model of HBV pathogenesis by a system of partial differential equations (PDEs) and use the model to simulate a 'synergy map' which addresses the above question.
Topics: Adenine; Computer Simulation; Diffusion; Drug Delivery Systems; Hepatic Stellate Cells; Hepatitis B virus; Hepatitis B, Chronic; Humans; Inflammation; Interferon-alpha; Liver Cirrhosis; Macrophages; Models, Theoretical; Organophosphonates; Th2 Cells
PubMed: 29634771
DOI: 10.1371/journal.pone.0195037 -
Biological & Pharmaceutical Bulletin 2023Uricosuric agents lower serum uric acid levels by increasing urinary excretion via inhibition of urate transporter 1 (URAT1), urate reabsorption transporter in the renal...
Uricosuric agents lower serum uric acid levels by increasing urinary excretion via inhibition of urate transporter 1 (URAT1), urate reabsorption transporter in the renal proximal tubules. Probenecid and benzbromarone have been used as uricosurics, but these drugs inhibit organic anion transporters (OATs) in addition to URAT1. In this study, we investigated whether uricosuric agents interacted with adefovir, known as a substrate for OAT1, using Sprague-Dawley (SD) rats. Furthermore, involvement of other transporters, multi-drug resistance protein 2 (MRP2) in this interaction was examined using Mrp2-deficient rats. Probenecid and lesinurad increased plasma adefovir concentrations and decreased kidney-to-plasma partition coefficient (Kp) in these rats, presumably by inhibiting Oat1. Although benzbromarone had no effect on plasma adefovir concentration, it increased the Kp to 141% in SD rats. Since this effect was abolished in Mrp2-deficient rats, together with the MRP2 inhibition study, it is suggested that benzbromarone inhibits Mrp2-mediated adefovir excretion from the kidney. In contrast, dotinurad, a novel uricosuric agent that selectively inhibits URAT1, had no effect on the plasma and kidney concentrations of adefovir. Therefore, due to the lack of interaction with adefovir, dotinurad is expected to have low drug-drug interaction risk mediated by OAT1, and also by MRP2.
Topics: Rats; Animals; Uricosuric Agents; Benzbromarone; Probenecid; Uric Acid; Rats, Sprague-Dawley; Kidney; Organic Anion Transporters
PubMed: 36724945
DOI: 10.1248/bpb.b22-00384 -
Alimentary Pharmacology & Therapeutics Jan 2004Chronic hepatitis B can be diagnosed in patients with increased aminotransferases, hepatitis B virus viraemia and necroinflammation with fibrosis on liver biopsy.... (Review)
Review
Chronic hepatitis B can be diagnosed in patients with increased aminotransferases, hepatitis B virus viraemia and necroinflammation with fibrosis on liver biopsy. Although, ideally, all patients with chronic hepatitis B should be treated, therapeutic intervention is currently recommended for cases with a relatively satisfactory likelihood of response and/or advanced disease. A realistic therapeutic approach aims to sustain hepatitis B e antigen (HBeAg) loss and hepatitis B e antibody (anti-HBe) seroconversion in HBeAg-positive chronic hepatitis B and to sustain biochemical and virological remission in HBeAg-negative chronic hepatitis B. Currently, three drugs are licensed for chronic hepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. In patients with HBeAg-positive chronic hepatitis B, all of these drugs achieve HBeAg loss (24-33%) and anti-HBe seroconversion (12-30%) rates significantly superior to those observed in untreated placebo controls. In patients with HBeAg-negative chronic hepatitis B, the sustained off-therapy response rate is 20-25% after a > or =12-month course of interferon-alpha and minimal (<10%), if any, after a 12-month course of lamivudine or adefovir. Long-term lamivudine induces an initial response in 70-90% of patients, but only 30-40% of patients remain in remission after the third year due to progressively increasing viral resistance. Long-term adefovir achieves a response in approximately 70% of patients at 12 months, which is maintained at 24 months with rare (<2%) drug resistance. Adefovir is also effective against lamivudine-resistant strains. Many other anti-viral agents, immunomodulatory approaches and combination therapies are currently being evaluated in chronic hepatitis B.
Topics: Antiviral Agents; Drug Resistance, Viral; Forecasting; Hepatitis B, Chronic; Humans; Retreatment; Treatment Outcome
PubMed: 14687164
DOI: 10.1046/j.1365-2036.2003.01810.x -
International Journal of Cancer Sep 2020Replication stress is a common feature of cancer cells. Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) signalling, a DNA damage repair (DDR) pathway, is...
Replication stress is a common feature of cancer cells. Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) signalling, a DNA damage repair (DDR) pathway, is activated by regions of single-stranded DNA (ssDNA) that can arise during replication stress. ATR delays cell cycle progression and prevents DNA replication fork collapse, which prohibits cell death and promotes proliferation. Several ATR inhibitors have been developed in order to restrain this protective mechanism in tumours. It is known, however, that despite other effective anticancer chemotherapy treatments targeting DDR pathways, resistance occurs. This begets the need to identify combination treatments to overcome resistance and prevent tumour cell growth. We conducted a drug screen to identify potential synergistic combination treatments by screening an ATR inhibitor (VE822) together with compounds from a bioactive small molecule library. The screen identified adefovir dipivoxil, a reverse transcriptase inhibitor and nucleoside analogue, as a compound that has increased cytotoxicity in the presence of ATR, but not ATM or DNA-dependant protein kinase (DNA-PK) inhibition. Here we demonstrate that adefovir dipivoxil induces DNA replication stress, activates ATR signalling and stalls cells in S phase. This simultaneous induction of replication stress and inhibition of ATR signalling lead to a marked increase in pan-nuclear γH2AX-positive cells, ssDNA accumulation and cell death, indicative of replication catastrophe.
Topics: Adenine; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Cell Death; Cell Line, Tumor; Cell Proliferation; DNA Replication; Humans; Organophosphonates; Protein Kinase Inhibitors; Signal Transduction
PubMed: 32159854
DOI: 10.1002/ijc.32966 -
La Revue Du Praticien Mar 2005Three drugs are currently available for the treatment of chronichepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. Standard interferon-alpha induces a... (Review)
Review
Three drugs are currently available for the treatment of chronichepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. Standard interferon-alpha induces a sustained response in only a minority of patients (10-30 %) and is associated with a poor tolerability which limits duration of therapy. The nucleoside (lamivudine) and nucleotide (adefovir dipivoxil) analogs have the advantages of oral administration and excellent tolerance. Lamivudine, administered for 12 months, induces a sustained response in approximately 20 % of the HbeAg positive and in 5 % of the HBeAg-negative patients. Long-term therapy increases the rate of sustained response but is impaired by a high rate of resistance (50 % at 3 years). Adefovir dipivoxil, administered for 12 months, induces a sustained response in 12 % of HBeAg-positive patients. Adefovir has a similar antiviral efficacy in HBeAg-negative patients. The incidence of resistance to adefovir is low (6 % at 3 years). Thus, the currently available drugs have a limited effectiveness and new more powerful drugs or new therapeutic strategies are necessary. Recent studies showed that the efficacy of pegylated interferon was higher than the standard interferon. Evaluated therapeutic combinations, pegylated interferon and lamivudine on the one hand and to adefovir and lamivudine on the other hand, did not show superiority as compared to the monotherapy by pegylated interferon and to adefovir, respectively. A number of nucleoside analogs, with favorable toxicity profiles and a promise of increased effectiveness against HBV, are at various stages of clinical development. Results of phase III trials of entecavir confirmed its efficacy and safety leading to registration in the next future. Emtricitabine does not seem more effective than lamivudine. The results of phase II studies of telbivudine and clevudine are promising. However, one may expect that their use in monotherapy could not induce a high rate of sustained response and that long-term therapy or combination should be needed to improve efficacy and/or reduce resistance.
Topics: Antiviral Agents; Hepatitis B, Chronic; Humans
PubMed: 15913114
DOI: No ID Found