| Objective:This study investigated the pharmacokinetics of tinidazole in subjects of five different Chinese nationalities (Han, Mongolian, Korean, Hui, and Uighur). Population modeling was performed using NONMEN (nonlinear mixed-effect modeling) program. The frequency of CYP3A4*18B genetic polymorphism was determined, and the impact of CYP3A4*18B genetic polymorphism on the pharmacokinetics of tinidazole was evaluated. The drug-interaction potential of tinidazole with the drug that inhibit CYP3A4 or induce it in rats was also studied. Finally, the research would provide instruction and help for the usage of tinidazole safely, reasonable and effectively to both clinic and remedy of battle wound.Methods:Fifty healthy subjects (five male and five female of each nationality) were recruited for the study, and each received 1 g tinidazole. A total of 14 blood samples were collected over a 72-hour period after administration. Estimates of pharmacokinetic parameters of tinidazole were obtained from DAS software. The pharmacokinetic parameters were compared by the methods of One-Way ANOVA and Nonparametric Test in SPSS. The population pharmacokinetic model of tinidazole was established for 50 healthy subjects of 650 samples. The effects of demography and biochemical covariates were investigated by NONMEM, including GENDER, RACE, AGE, HT, WT, BMI, ALT, BUN and SCR. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied to detect the frequency of CYP3A4*18B gene polymorphism in 100 healthy Han subjects. Blood samples were collected from nine CYP3A4*18B/*1 genotype subjects and ten CYP3A4*1/*1 genotype subjects. Estimates of pharmacokinetic parameters of tinidazole were obtained from DAS software. The pharmacokinetic parameters of two groups were compared by the methods of Independent-Samples T Test and Nonparametric Test in SPSS. The drug-interaction potential of tinidazole with the drug that inhibit CYP3A4 or induce it in rats was also studied. The effect of clarithromycin and dexamethasone acetate on the pharmacokinetic of tinidazole in rats was detected. Fifteen rats were randomly divided into three equal groups: Group A and group B were given clarithromycin or dexamethasone acetate for five days, and tinidazole was given at the sixth day with them, group C was given tinidazole. Blood samples were taken from the animals for the determination of the plasma concentration of tinidazole by HPLC. The pharmacokinetics parameters were calculated by DAS software and were compared by SPSS software.Results:The pharmacokinetic parameters of Han, Mongolian, Korean, Hui, and Uighur healthy subjects were as follows:Cmax:(19.04±2.42)、(19.22±4.93)、(20.83±3.33)、(20.25±4.05)、(18.81±3.10) mg·L-1; tmax:(2.15±0.47)、(2.20±0.59)、(2.30±0.63) (2.10±0.66)、(2.25±0.54) h; t1/2:(16.94±2.40)、(16.39±1.79)、(16.63±1.82) (16.81±1.56)、(14.34±1.92) h; Vd/F:(51.01±9.49)、(51.18±11.72)、(47.53±7.64) (49.21±9.33)、(53.63±8.68) L; CL/F:(2.09±0.29)、(2.16±0.42)、(1.98±0.22) (2.06±0.50)、(2.59±0.24)L·h;AUC0-∞:(486.14±65.63)、(479.70±99.75)、(511.07±53.47)、(514.25±130.78)、(388.58±37.37) mg·h·L-1. One-Way ANOVA was used to compare the pharmacokinetic parameters t1/2、Ke、Vd/F and Ka, and A nonparametric rank test was used to compare Cmax、AUC0-∞、CL/F、tmax. The results showed that the t1/2, AUC0-∞, CL/F and Ke values were significantly different between Uighur and other nationalities in China. The analysis of covariates were included to control for weight.The population pharmacokinetic (PPK) model of tinidazole was performed using NONMEN program, based on a two-compartment. The PPK model of tinidazole was established and expressed as follows:(Cl1/F)i=(0.807×2.49(WTi/57.14)+θCl1-RACE)×eηCl1i(L·h-1)(Cl2/F)i=205×eηCl2i(L·h-1)(V1)i=(3.29+θV1-RACE)×2.11GENDER×eηv1i(L)(V2)i=(19.0×2.32(WTi/57.14))×eηv2i(L)(Ka)i=1.51×eηKai(h-1) Tlag＝0.216(h)The results showed that gender and race had significant differences on the V1, weight had significant differences on the V2, and weight and race had significant differences on the CL1.PCR-RFLP method was applied to detect the frequency of CYP3A4*18B gene polymorphisms in 100 healthy Han subjects.88 CYP3A4*1/*1 genotype and 12 CYP3A4*1/*18B were founded in this study. The frequency of CYP3A4*18B allele was 6%. The genotype frequency was consistent with Harding-Weinberg equilibrium. The pharmacokinetic parameters of CYP3A4*1/*1 genotype and CYP3A4*1/*18B genotype healthy subjects were as follows:t1/2 :(15.92±1.62)、(15.77±1.67) h; Cmax:(18.72±3.10)、(20.25±3.42) mg·L-1; tmax:(1.50±0.66)、(1.45±0.69) h; Vd/F:(55.73±10.66)、(51.30±7.75) L; CL/F:(2.44±0.47)、(2.26±0.30) L·h; AUC0-∞:(424.40±82.38)、(450.53±69.48) mg·h·L-1. There were no significant differences between the two groups.The pharmacokinetic parameters of group A (clarithromycin and tinidazole), group B (dexamethasone acetate and tinidazole), and group C (tinidazole) were as follows:t1/2: (2.76±1.69)、(1.95±0.31)、(2.16±0.76) h; Cmax:(32.73±8.37)、(23.69±3.45)、(27.08±2.98) mg·L-1; tmax:(1.00±0.35)、(1.05±0.62)、(1.10±0.22) h; Vd/F:(0.41±0.22)、(0.41±0.05)、(0.38±0.13) L; CL/F:(0.11±0.006)、(0.15±0.01)、(0.12±0.005) L·h; AUC0-∞:(172.23±10.98)、(124.74±12.13)、(145.89±6.14) mg·h·L-1. The results of Independent-Samples T Test showed that CL/F and AUC0-∞had significant differences between A and C, also between group B and C.Conclusions:The pharmacokinetic parameters showed differences among Han, Mongolian, Korean, Hui, and Uighur healthy subjects after a single oral dose of 1 g tinidazole. The clearance of tinidazole in Uighur subjects was higher than other nationalities. The population pharmacokinetic model of tinidazole was established, and the results showed that gender, race and weight had significant differences on the pharmacokinetice of tinidazole. The frequency of CYP3A4*18B allele was 6%, and there were no significant difference between the CYP3A4*1/*1 genotype group and CYP3A4*1/*18B genotype group. Both clarithromycin and dexamethasone acetate have significant differences on the pharmacokinetic of tinidazole in rats. |
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