The most important dose-limiting factor of the anthracycline idarubicin is the high risk of cardiotoxicity, in which the secondary alcohol metabolite idarubicinol plays an important role. It is not yet clear which enzymes are most important for the formation of idarubicinol and which inhibitors might be suitable to suppress this metabolic step and thus would be promising concomitant drugs to reduce idarubicin-associated cardiotoxicity. We, therefore, established and validated a mass spectrometry method for intracellular quantification of idarubicin and idarubicinol and investigated idarubicinol formation in different cell lines and its inhibition by known inhibitors of the aldo-keto reductases AKR1A1, AKR1B1, and AKR1C3 and the carbonyl reductases CBR1/3. The enzyme expression pattern differed among the cell lines with dominant expression of CBR1/3 in HEK293 and MCF-7 and very high expression of AKR1C3 in HepG2 cells. In HEK293 and MCF-7 cells, menadione was the most potent inhibitor (IC50 = 1.6 and 9.8 µM), while in HepG2 cells, ranirestat was most potent (IC50 = 0.4 µM), suggesting that ranirestat is not a selective AKR1B1 inhibitor, but also an AKR1C3 inhibitor. Over-expression of AKR1C3 verified the importance of AKR1C3 for idarubicinol formation and showed that ranirestat is also a potent inhibitor of this enzyme. Taken together, our study underlines the importance of AKR1C3 and CBR1 for the reduction of idarubicin and identifies potent inhibitors of metabolic formation of the cardiotoxic idarubicinol, which should now be tested in vivo to evaluate whether such combinations can increase the cardiac safety of idarubicin therapies while preserving its efficacy.

Ranirestat, an aldose reductase inhibitor evaluated in several randomised controlled trials (RCTs) in diabetic peripheral neuropathy (DPN). However, to date, no meta-analysis has evaluated the efficacy and safety of ranirestat in DPN. We undertook this meta-analysis to address this knowledge gap. Detailed search of electronic databases for RCTs published till December 2021 was done at Cochrane register, Medline, PubMed, Embase, clinicaltrials.gov, ctri.nic.in, global health and Google Scholar using the Boolean search strategy: ((ranirestat) OR (aldose reductase inhibitor)) AND ((diabetes) OR (\"diabetes mellitus\")). The primary outcome was to evaluate changes in nerve conduction velocities (NCV) of different nerves. The secondary outcomes were to evaluate alterations in amplitudes, F-wave latencies of nerves, modified Toronto Clinical Neuropathy Score (mTCNS) and adverse events. Data from 5 studies involving 1461 patients with DPN was analysed to establish the impact of ranirestat (20-40 mg/day) as compared to placebo on different electrophysiologic outcomes over a median follow-up of 52 weeks. Patients receiving ranirestat had significantly greater improvement in proximal median sensory NCV [MD 0.77 m/s (95%CI: 0.50-1.05); P < 0.01; I2 = 26%], distal median sensory NCV [MD 0.91 m/s (95%CI: 0.87-0.95); P < 0.01; I2 = 0%], median motor NCV [MD 0.63 m/s (95%CI: 0.60-0.66); P < 0.01; I2 = 0%], tibial motor NCV [MD 0.46 m/s (95%CI: 0.43-0.49); P < 0.01; I2 = 0%] and peroneal motor NCV [MD 0.80 m/s (95%CI: 0.66-0.93); P < 0.01; I2 = 0%]. mTCNS was not significantly different among groups. Treatment-emergent adverse events [risk ratio (RR) 0.85 (95%CI: 0.63-1.14); P = 0.28; I2 = 0%] and severe adverse events [RR 1.35 (95%CI: 0.86-2.11); P = 0.20; I2 = 0%] were comparable across study groups. In people with established DPN with long-standing diabetes, ranirestat is safe and effective in improving electrophysiologic but not clinical DPN.

Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open-label, single-dose, parallel-group study was conducted to compare pharmacokinetic (PK) characteristics of an oral dose of ranirestat across subjects with normal hepatic function and patients with mild and moderate hepatic impairment because ranirestat is expected to be used by patients with diabetes mellitus, possibly including those with hepatic impairment. To evaluate the necessity for dose adjustment, PK profiles and tolerability were studied at the dose of 40 mg, the expected optimal clinical dose in patients with diabetic neuropathy and normal hepatic function. In total, 20 subjects, including 5, 10, and 5 subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively, completed the study. Serial PK sampling was conducted up to 504 hours, and PK parameters were calculated and compared between healthy subjects and patients with mild or moderate hepatic impairment. The geometric mean ratios of peak concentration and area under the concentration-time curve in patients with mild hepatic impairment (90%CI) were 86.7% (55.3% to 135.9%) and 84.7% (68.5% to 104.8%), respectively. The values in patients with moderate hepatic impairment were 81.3% (48.8% to 135.5%) and 91.7% (72.1% to 116.7%), respectively. These results demonstrated that plasma ranirestat exposure and the plasma protein binding of the drug were not substantially altered by normal, mild, or moderate hepatic impairment (protein binding 99.22%, 99.29%, and 99.00%, respectively). All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment.

OBJECTIVE: Diabetic polyneuropathy is one of the most frequent diabetic complications, and impairs patients\' quality of life. We evaluated the efficacy and safety of ranirestat (40 mg/day) in patients with diabetic polyneuropathy.
METHODS: This was a multicenter, placebo-controlled, randomized double-blind, parallel-group, phase III study in which 557 patients were randomly assigned to either the ranirestat or placebo group and assessed for 52 weeks. The co-primary end-points were the changes in tibial motor nerve conduction velocity and total modified Toronto Clinical Neuropathy Score as a measure of clinical symptoms.
RESULTS: There was a significant increase in tibial motor nerve conduction velocity in the ranirestat group compared with the placebo group. The difference between groups in the change at last observation was 0.52 m/s (P = 0.021). Increases in nerve conduction velocity in the ranirestat group were found not only in the tibial motor nerves, but also in the median motor nerves, proximal median sensory nerves and distal median sensory nerves. No significant differences in modified Toronto Clinical Neuropathy Score or safety parameters were found between the two groups.
CONCLUSIONS: Ranirestat (40 mg/day) was well tolerated and improved nerve conduction velocity. Regarding symptoms and signs, no detectable benefits over the placebo were observed in the ranirestat group during the 52 weeks of treatment.

BACKGROUND: Pharmacologic maintenance of normoglycemia in diabetes cannot prevent the eventual complications mainly due to protein glycation-induced cell death, dysregulated antioxidant defense and signal transduction in affected tissues. The rate-limiting enzyme of this process, aldose reductase, is therefore a pharmacologic target. To date, nine inhibitors of this enzyme have been developed. Ranirestat has completed two Phase III clinical trials. The objective of this evaluation is to summarize and provide expert opinion on the status of ranirestat with an emphasis on its pharmacokinetics in the context of its potential effects to prevent/treat diabetic complications.
METHODS: A qualitative systematic literature search of PubMed through November 2013 using MeSH terms - aldose reductase inhibitors, diabetic neuropathy, AS-3201, ranirestat, diabetic complications and pharmacokinetics/pharmacodynamics - identified relevant publications limited to human and rodent (mouse and rat) and English-language studies.
CONCLUSIONS: Ranirestat is a well-tolerated front-line inhibitor. It reproducibly exhibits some degree of measurable objective beneficial outcomes in diabetic neuropathy. It is the furthest advanced in clinical trials with some depth of supporting preclinical data. Trials in subjects with newly diagnosed neuropathy along with the identification of objective biomarkers/measurements of efficacy will be critical in identifying the real value and effect of ranirestat.