The Pharmacokinetic Study Of Imidol Hydrochloride

Imidol hydrochloride was a new excellent anti-Hepatitis B Virus drug with its chemical name of 1-methyl-4-(1-imidazole)methyl-2-(phenyl-sulfinylmethyl)-5-hydroxy-6-bromo-lH-indole-3-carboxylic acid ethyl ester hydrochloride. Imidol hydrochloride is a new anti-viral drug appealed as a class I new drug, which was investigated and developed in our country. With perfect development prospect, imidol has not been seen teratogenesis, mutagenesis, obvious toxicity in long-term toxicity and reproductive toxicity study, and it has a low synthetic cost.1. The stability study of imidolIn this paper, a RP-HPLC method was developed to determine the concentration of imidol hydrochloride. The effect of temperature, pH and light on the stability of imidol and the effect of different biological matrix were assessed. The concept of chemical kinetics and Arrhenius equations were introduced to investigate the degradation kinetics of imidol in aqueous solutions at different pH (pH 1.5,3.0,5.2,7.4,9.0,11.0) with 37℃. The results were In CA=-0.02570t+4.279, r=0.9338; In CA=-0.02790t+1.156, r=0.9337; In CA=-0.030501+0.07820, r=0.9348; In CA=-0.047501+3.622, r=0.9621; In CA=-0.20771 +1.828, r=0.9718 and In CA=-0.4143 t+2.004, r=0.9431; t12 were 27.0,24.8,22.7, 14.6,3.3,1.7 h respectively. The degradation kinetics equations at different temperature(0℃,20℃,37℃,70℃,100℃)were:In CA=-0.02920 t+4.402, r=0.9380, In CA=-0.04750 t+3.622, r=0.9621; In CA=-0.05540 t+2.557, r=0.9156; In CA=-0.3980 t+1.318, r=0.9016; In CA=-0.4844 t+2.621, r=0.9653 and the corresponding values of t12 were 23.7,14.6,12.5,1.7,1.4 h, respectively. The degradation kinetics equation on light was, In CA=-0.01350 t+4.012, r=0.9014;In different biological matrix (urine, bile, plasma) the degradation kinetics equations were, In CA=-0.02059 t+4.513, r = 0.9775; In CA=-0.04680 t+6.022, r=0.9753; In CA=-0.03070 t+4.416, r=0.9585, respectively; and the t12 were 33.6,14.8,22.6 h, respectively.This study revealed that the degradation of imidol is effected by temperature, pH and light. So in the biological sample collection and preservation process of imidol in order to prevent the degradation of imidol, we should avoid too high pH solution, high temperature and contact of glare as far as possible.2. The pharmacokinetic study of imidol in ratsA rapid, accurate and sensitive UPLC-MS-MS method, with an LLOQ (Low Limit of Quantitation) of 2.518 ng·mL-1, was developed and fully validated for the pharmacokinetic study of imidol in rats. The pharmacokinetic processes of imidol in rats after intravenous injection (10.02 mg·kg-1) and oral administration with different doses (10.02,30.25, 70.55 and 320.3 mg·kg-1) were investigated. With the oral doses of 10.02,30.25,70.55 and 320.3 mg·kg-1, Tmax were 0.4±0.1,0.4±0.1,0.4±0.1 and 0.4±0.1 h; Cmax were 64.79±6.44,188.1±29.4,660.2±174.9,4430±1288 ng·mL-1; AUC0-t were 80.1±7.5, 269.3±53.4,769.4±77.8 and 6130±2063 ng·h·mL-1; AUC0-∞were 93.8±11.1, 287.0±62.2,827±97 and 6410±2022ng·h·mL-1; T1/2 were 5.4±1.2,3.4±0.6,4.0±1.0 and 4.1±1.4 h, respectively. After intravenous injection of 10.02 mg·kg-1, the drug reached its maximum concentration of 1896±634 ng·mL-1; AUC0-t and AUC0-∞, were 500.8±83.2 and 534.5±71.76 ng·h·mL-1, respectively; t1/2 was 4.1±1.5 h. The parameters obtained were then compared and analyzed. Dose-dependent linear relationships of AUCo-t and Cmax for imidol was found in the range of 10.02 to 70.55 mg·kg-1 after oral administration to rats. t1/2 from each group showed no significant difference by rank sum test. Bioavailability of this drug was determined as 17.55%.3. The metabolite study of imidol in rats and liver microsomesThe MS fragmentation pathways of imidol by ESI source were studied and summarized with UPLC-MS-MS method. The result Was quite essential and helpful for the further drug metabolism investigation.The UPLC-MS-MS system was used for the identification of imidol metabolites from rat feces, urine and plasma samples. There were altogether 8 metabilites detected and identified in vivo bio transformation products, including 3 phase I ones and 5 phase II ones. There were altogether 3 metabilites detected and identified in vitro biotransformation products. They are all phase I ones. It is concluded that imidol metabolism was mainly accomplished such as N-demethyl,S-oxidation and O-conjugation with Glu or SO3.4. The excretion study of imidol in ratsThe excretion of imidol from rats after an oral administration of 70.55 mg·kg-1 was investigated. The cumulative amount for imidol was 2808±856μgμg in feces within 72 h after administration, which amounted to 20.06% of the given dosage. In urine, the cumulative amount was only 8.14±2.62 ng, indicating a minor urinary excretion of the parent compound. The excretion of imidol from bile was slight and constant, with the cumulative amount of 18.79±3.78 ng. The data above suggested that most of the drug administrated has been metabolized, and enteropatic recycling of imidol is weak in rats.