ABSTRACT
Epalrestat is clinically applied for the management of diabetic peripheral neuropathy, yet its pharmacokinetic properties are not well understood. In this study, a rapid and sensitive LC-MS/MS method was established for assaying epalrestat in bio-samples of mice. The method was validated and it showed a good linearity over the range of 2-5000ng/mL, a precision of less than 12.3%, and recovery and matrix effects of 112.5-123.6% and 87.9-89.5%, respectively. After administration of a single dose of epalrestat administered, the exposure level of AUC0-∞ was positively dose-dependent and the mean Cmax, AUC0-12h, T1/2, and MRT were 36.23±7.39µg/mL, 29,086.5µg/Lh, 1.2h and 1.8h, respectively. Epalrestat was highly exposed in stomach, intestine, liver and kidney, and only a small amount was detected in brain, urine and feces. Multi-dose of epalrestat significantly increased MRT and apparent volume of distribution (Vd) relative to those of a single-dose.
Subject(s)
Chromatography, High Pressure Liquid/methods , Enzyme Inhibitors/pharmacokinetics , Rhodanine/analogs & derivatives , Thiazolidines/pharmacokinetics , Administration, Oral , Animals , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/blood , Enzyme Inhibitors/urine , Female , Limit of Detection , Male , Mice, Inbred C57BL , Rhodanine/administration & dosage , Rhodanine/blood , Rhodanine/pharmacokinetics , Rhodanine/urine , Spectrometry, Mass, Electrospray Ionization/methods , Thiazolidines/administration & dosage , Thiazolidines/blood , Thiazolidines/urine , Tissue DistributionABSTRACT
In the present study, a simple, rapid and reliable ultrahigh-performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method was developed and validated to determine simultaneously epalrestat (EPA) and puerarin (PUE) in rat plasma for evaluation of the pharmacokinetic interaction of these two drugs. Both the analytes and glipizide (internal standard, IS) were extracted using a protein precipitation method. The separation was performed on a C18 reversed phase column using acetonitrile and 5 mmol/L ammonium acetate in water as the mobile phase with a gradient elution program. The analytes, including IS, were quantified with multiple reaction monitoring under negative ionization mode. The optimized mass transition ion pairs (m/z) were 318.1 â 274.0 for EPA, 415.1 â 266.9 for PUE and 444.2 â 166.9 for IS. The linear calibration curves for EPA and PUE were obtained in the concentration ranges of 10-4167 and 20-8333 ng/mL, respectively (r > 0.99). The current method was successfully applied for the pharmacokinetic interaction study in rats following administration of EPA and PUE alone or co-administration (EPA 15 mg/kg, oral; PUE 30 mg/kg, intravenous). The results showed that the combination of EPA and PUE could increase t1/2 of EPA and reduce Tmax of EPA. These changes indicated that EPA and PUE might cause drug-drug interactions when co-administrated.
Subject(s)
Chromatography, Liquid/methods , Isoflavones/blood , Isoflavones/pharmacokinetics , Rhodanine/analogs & derivatives , Tandem Mass Spectrometry/methods , Thiazolidines/blood , Thiazolidines/pharmacokinetics , Animals , Drug Interactions , Drug Stability , Female , Limit of Detection , Male , Rats, Wistar , Reproducibility of Results , Rhodanine/blood , Rhodanine/pharmacokineticsABSTRACT
A simple and rapid LC-MS/MS method was developed and validated for the quantification of epalrestat, an aldose reductase inhibitor for the treatment of diabetic neuropathy. Following protein precipitation epalrestat and IS were eluted with 10mM ammonium acetate and acetonitrile using a rapid gradient program on reverse phase column. Multiple reaction monitoring mode was used to monitor the transitions of m/z 318â58 for epalrestat and m/z 410â348 for the IS. The assay exhibited a linear dynamic range of 2-5,000 ng/mL for epalrestat in rat plasma. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The within batch accuracy was in the range of 101.3-108.0% with precision in the range of 3.0-12.3%. All the other validation parameters were within the acceptable limits. Validated method was applied to analyze rat plasma samples obtained from a pharmacokinetic study. After oral administration of epalrestat at 10mg/kg to wistar rats (n=3) mean C(max), AUC(0-24) (ngh/mL) and t(1/2) were found to be 4077 ± 1327 ng/mL, 8989 ± 1590 ngh/mL and 2.9 ± 1.4h, respectively. Bioavailability was found to be 90 ± 14% for epalrestat in male wistar rats.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Aldehyde Reductase/blood , Rhodanine/analogs & derivatives , Tandem Mass Spectrometry/methods , Thiazolidines/blood , Thiazolidines/pharmacokinetics , Animals , Chromatography, Liquid/methods , Enzyme Inhibitors/blood , Enzyme Inhibitors/pharmacokinetics , Male , Rats , Rats, Wistar , Rhodanine/blood , Rhodanine/pharmacokineticsABSTRACT
In patients with malignant tumors, autoaggression diseases and following transplantations the blood rhodanide level was found to increase; a correlation with the results of the MEM test was established.