Pharmacokinetics of isoniazid in Wistar rats exposed to ethanol

Abstract Tuberculosis treatment consists of a drug combination, where isoniazid is the core drug and alcoholism is a factor highly related to poor patient compliance with the therapy. CYP2E1 is an enzyme involved both in the metabolism of ethanol and in the formation of hepatotoxic compounds during the metabolism of isoniazid. The shared metabolism pathway accounts for the possibility of pharmacokinetic interaction in cases of concomitant alcohol use during tuberculosis treatment. The aim of this study was to evaluate the effect of repeated exposure of Wistar rats (males, 250 g, n=6) to ethanol on the pharmacokinetics of a single dose of isoniazid in combination with pyrazinamide and rifampicin (100 mg/kg, 350 mg/kg and 100 mg/kg, respectively). An animal group received the combination of drugs and ethanol and was compared to a control group, which received the combination of drugs without exposure to ethanol. The plasma concentrations of isoniazid were determined by a UHPLC/UV bioanalytical method that was previously validated. Biochemical markers of liver function were measured to assess potential damage. A lower elimination half-life of isoniazid was observed in the ethanol group than in the control group (t1/2 0.91 h versus 1.34 h). There was no evidence of hepatotoxicity through the biomarker enzymes evaluated. The results allow us to infer that although there are no biochemical changes related to liver damage, there is a slight influence of ethanol exposure on the pharmacokinetic profile of isoniazid. This change may have a relevant impact on the efficacy of isoniazid in the outcome of tuberculosis treatment.

UHPLC Quantitation Method for New Thiazolidinedione LPSF/GQ-02 and In Vitro/In Vivo Kinetic Studies.

BACKGROUND: LPSF/GQ-02 is a promising benzylidene thiazolidinedione that has demonstrated antidiabetic, antidyslipidemic, anti-atherosclerotic properties and can also treat non-alcoholic fatty liver disease. Despite all activity studies of the new compound, its pharmacokinetics are not yet described. OBJECTIVE: The aim of this study was to perform its first pharmacokinetic profile. METHODS: For this purpose a bioanalytical method for the quantitation of 5-(4- Chloro-benzylidene)-3-(4-methylbenzyl)-thiazolidine-2,4-dione (LPSF/GQ-02) was developed and validated. A Waters UPLC chromatographer using a BEH column (2.1x50mm, 1.7µm particle), mobile phase water:acetonitrile (20:80) was used. The range of calibration curve in plasma was 1.9 to 250 ng/mL with r = 0.9997. LPSF/GQ-02 stability was evaluated in rat plasma and buffers at pH 1.2 and 7.4. The pharmacokinetic assay was carried out in male Wistar rats weighing 250-300 g. The animals received LPSF/GQ-02 at 3 mg/kg by intravenous route. The animals were used to perform a preliminary safety study concerning the evaluation of liver and kidney biomarkers (ALT, AST, urea, creatinine). RESULTS: The obtained pharmacokinetic parameters were elimination half-life of 4.44 h, Cl of 8.00 L/h.kg, Vd of 45.60 L/kg and MRT of 3.79h. No difference was observed for the liver and kidney biomarkers. CONCLUSION: The intravenous pharmacokinetic parameters are in agreement with a good future posology, even though the plasma concentrations from oral administration were not quantifiable in a dose of 12 mg/kg. The preliminary safety study demonstrated no acute effect of the drug in liver and kidneys. The LPSF/GQ-02 is a new thiazolidinedione that should continue being evaluated for future clinical use.

Pharmacokinetics of hydroxymethylnitrofurazone and its parent drug nitrofurazone in rabbits.

The prodrug hydroximethylnitrofurazone (NFOH) presents antichagasic activity with greatly reduced toxicity compared to its drug matrix nitrofurazone (NF). Besides these new characteristics, the prodrug was more active against the parasite T. cruzi amastigotes. These advantages make the prodrug a possible therapeutic alternative for the treatment of both acute and the chronic phase of Chagas disease. However, the knowledge of pharmacokinetic profile is crucial to evaluate the feasibility of a new drug. In this study, our objective was to evaluate the in vivo formation of NF from the NFOH single administration and to evaluate its pharmacokinetic profile and compared it to NF administration. A bioanalytical method to determine the NF and NFOH by LCMS/MS was developed and validated to perform these investigations. Male albino rabbits (n=15) received NF intravenously and orally in doses of 6.35 and 63.5 mg / kg respectively, and NFOH, 80.5 mg / kg orally. The serial blood samples were processed and analyzed by mass spectrometry. The system operated in positive and negative modes for the analites determination, under elution of the mobile phase 50:50 water: methanol. The administration of NFOH allowed the calculation of pharmacokinetic parameters for the prodrug, and the NF obtained from NFOH administration. Using the pharmacokinetic profile obtained from the NF i.v. administration, the oral bioavailability of NF from the administered prodrug was obtained (60.1%) and, as a key parameter in a prodrug administration, should be considered in future studies. The i.v. and oral administrations of NF differ in the constant of elimination (0.04 vs 0.002) and elimination half-life (17.32 min vs 276.09 min) due to the low solubility of the drug that hinders the formation of molecular dispersions in the digestory tract. Still, there was observed no statistical differences were observed between the pharmacokinetic parameters of orally administered NF and NF obtained from NFOH. The calculated area under the curve (AUC 0-∞) showed that the exposure to the parental drug was fairly the same (844.79 vs 566.44) for NF and NF obtained from the prodrug administration. The tendency to higher NF's mean residence time (MRT) as observed in the prodrug administration (956.1 min vs 496.3 min) guarantees longer time for the action of the drug and it allows the expansion of the administration intervals. These findings, added with the beneficial characteristics of the prodrug encourage new efficacy tests towards the clinical use of NFOH.