| Imidol hydrochloride tablet is a novel drug for the treatment of hepatitis B virus ?HBV?infection. In this paper, methods for concentration assay of this drug in human plasma,urine and feces were developed, and the pharmacokinetic processes and the identification of metabolites of imidol in health volunteers were systematically studied. Besides,the effects of cytochrome P450 ?CYP450? on the metabolism of imidol in HLM, and whether the pharmacokinetics of imidol is dependent on the genotype status in Chinese healthy subjects were investigated, too.1 Pharmacokinetic study of imidol hydrochloride tablet in Chinese healthy subjectsA rapid, accurate and sensitive solid-phase extraction ?SPE? liquid chromatography-tandem mass spectrometry ?LC-MS/MS? method for determination imidol in human plasma, urine and feces was developed and fully validated for the first time. The LLOQ of the method was 0.2016 ng·mL-1,and the mean recovery of SPE was 87.6 %. The established method for the determination of imidol in matrix laid the root for following study.The pharmacokinetics of imidol in health volunteers was investigated. After the determination of imidol in plasma, the single-dose and the multiple-dose pharmacokinetics of imidol in Chinese healthy volunteers were estimated.For the pharmacokinetic study after single-dose oral administration,thirty healthy volunteers were enrolled, and divided into three groups at random. For each group, oral administration of 200 mg, 400 mg and 800 mg were adopted, respectively. After oral administration of single dose of 200 mg, the pharmacokinetic process of drug in human was characterized: Tmax ?h? was 0.85 ± 0.43, Cmax (ng·mL-1) was 683.4 ± 359.4, t1/2 ?h? was 9.43 ± 4.72,AUC0-t (ng·h·mL-1) was 995 ± 401,AUC0-? (ng·h·mL-1) was1013 ± 406,respectively. Ten healthy volunteers were given imidol hydrochloride tablet 400mg administered with food or in fasted state by a random crossover study design, the pharmacokinetic parameters were as follows: Tmax ?h? were 1.30 ± 1.10 and 0.73 ± 0.22,Cmax (ng·mL-1) were 472.6 ± 455.1 and 1164 ± 558, t1/2 ?h? were 12.02 ± 7.51 and 7.44 ±3.39,AUC0-t (ng·h·mL-1) were 946± 711 and 1637 ± 706, AUC0-? (ng·h·mL-1) were 961 ±708 and 1648 ± 709, respectively. After oral administration of single doses of 800 mg, the pharmacokinetic parameters were investigated,Tmax ?h? was 0.85 ± 0.13,Cmax (ng·mL-1)was 3103 ± 704, t1/2 ?h? was 8.96 ± 3.33, AUC0-t (ng·h·mL-1) was 5021 ± 1095, AUC0-?(ng·h·mL-1) was 5065 ± 1087, respectively.The ANOVA and linear regression were applied for the main pharmacokinetic parameters among three different groups. AUC0-t, AUC0-? and Cmax increased in proportional to the dosages and the differences of Tmax or t1/2 are not significant. Imidol undergoes linear pharmacokinetic characteristics in the dose range of 200 ?800 mg. Cmax and AUC-t of imidol administered with food were 40.61 % and 57.75 % of that in fasted state,respectively. Food affects the exposure of imidol.For the pharmacokinetic study after multiple-dose oral administration, twenty healthy volunteers were enrolled, and divided into two groups at random and underwent oral administration of multiple doses of 600 mg or 800 mg twice daily for 14 days. The plateau concentration was achieved after 14 days. On the 15th day, the pharmacokinetic parameters were investigated, Tmax ?h? were 0.78 ± 0.23 and 0.60 ± 0.21,Css max (ng·mL-1) were 812 ±402 and 1554 ± 394, t1/2 ?h? were 9.66 ± 7.80 and 7.25 ± 2.43, AUCss (ng-h·mL-1) were 11144 ± 510 and 2000 ± 542, DF ?%? were 8.33 ± 1.13 and 9.24 ± 1.26. As the main pharmacokinetic parameters of single-dose and multiple-dose oral administration, Tmax and t1/2 didn't show significant difference, which indicated that the absorption and elimination of imidol didn't change with dosage regimen in this study. When the dosage regimens were adopted, imidol not underwent accumulation in human body.2 Study on the metabolism of imidol hydrochloride tablet in human and human liver microsomesThe MS/MS fragmentation pathways of imidol by ESI source were studied and summarized with quadrupole linear ion trap mass spectrometry ?Q-Trap? method. The result was quite essential and helpful for the later drug metabolism investigation.The liquid chromatography-electrospray ionization ?ESI? ion Q-Trap mass spectrometry system was used for the identification of imidol metabolites from human feces, urine and plasma samples. There were altogether 11 metabilites detected and identified, including 3 phase ? biotransformation products and 8 phase ? ones. It is concluded that imidol metabolism was mainly accomplished in liver, after metabolic reactions such as N-demethylation, S-oxidation and O-conjugation with Glu or SO3, the metabolites were mainly got out of the human body in feces. The major metabolite identified was glucuronide imidol.A rapid LC-MS/MS method was developed for the detection of imidol in human liver microsomes. The calibration curve of peak areas versus the concentration was linear over the range of 002 ? 2.0?mol·L-1.Precision and accuracy of the method were also validated.CYP450 isoforms involved in the metabolism of imidol were studied by using selective CYP450 enzyme inhibitors. Our results showed that three CYP450 isoforms including CYP1A2, CYP2A6 and CYP3A4/5 were found involved in the metabolism of imidol.3 Study on the excretion of imidol hydrochloride tablet in humanThe excretion of imidol from human being after an oral administration was investigated.The cumulative amount for imidol in feces and urine were amounted to 16.54 % and 0.10% of the given dosage, respectively. The drug administrated was mainly excreted from the human urine within 0?4 h period, and the amounts excreted over 4 h were small and slow.The data above suggested that most of the drug administrated has been metabolized.4 Effects of genetic polymorphism on the pharmacokinetics of imidol hydrochlorideInvestigate the distribution of genetie Polymorphisms of CYP2A6, CYP3A5, NR1I2,MDR1 and UGT1A1 in Chinese population, and analyze their effects on the metabolism of imidol. The genetic polymorphism of CYP2A6, CYP3A5, NR1I2, MDR1 have not influenced the pharmacokinetics of imidol. The genotype of UGT1A1 may be responsible in individual variability of imidol pharmacokinetics. This subject can offer molecular level explaining for individual difference of imidol, and guide personalized medicine. |
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