Genetic analysis of N-acetyltransferase polymorphism in a Chinese population.

AIM: To study the genetic basis of N-acetylatransferase polymorphism in Chinese. METHODS: Genotypes in 120 healthy Han volunteers from 19 provinces of China were assayed. The 3 common mutant alleles (M1, M2, M3) and one normal wild-type (WT) allele of the N-acetyltransferase (NAT2) gene were detected by allele-specific polymerase chain reaction technique. RESULTS: The NAT2 allele frequencies in 120 Chinese (WT = 0.625, M1 = 0.0458, M2 = 0.188, M3 = 0.142) were different (P < 0.01). The NAT2 genotype distribution for all detected combinations of NAT2 alleles in 120 Chinese subjects was consisitent with Hardy-Weinberg equilibrium (chi 2 = 7.27, nu = 8, 0.7 > P > 0.5). Fifty subjects (41.7%) were homozygous wildtypes, 50 subjects (41.7%) were heterozygous mutants, and 20 subjects (16.7%) were homozygous mutants. CONCLUSION: The lower frequency of mutant M1 allele compared with that of Caucasians explains the low frequency of slow acylators in Chinese.

Pharmacokinetics of theophylline metabolites in 8 Chinese patients.

AIM: To study theophylline metabolites pharmacokinetics in patients after a therapeutic dose. METHODS: Eight adult patients with mild bronchial asthma and normal liver function were infused aminophylline intravenously (6.6 mumol.kg-1). The plasma concentrations of theophylline and its 4 metabolites: 1,3-dimethyluric acid (DMUA), 3-methylxanthine (3-MX), 1-methyluric acid (MUA), and the intermediate 1-methylxanthine (1-MX) were monitored by HPLC throughout 24 h. RESULTS: The plasma concentration of DMUA was the highest one among the 4 metabolites. 3-MX showed the slowest elimination rate. The plasma concentration of 1-MX throughout a 24-h period showed that there was a picking up of 1-MX (from 0.04 mumol.L-1 to 1.05 mumol.L-1) in the next morning. CONCLUSION: The formation of DMUA was the main metabolites. During night there was an accumulation of 1-MX.

[HPLC determination of five caffeine metabolites].

An HPLC method for the determination of caffeine metabolites in urine was established. Shim Pack CLC-ODS column (5 microns) was eluted with the mobile phase of methanol--acetonitrile--0.05% acetic acid = 12:1:87 (v/v) at a flow rate of 1.2 ml.min-1, and the ultraviolet absorbance was monitored at 280 nm. The 13 caffeine metabolites and caffeine were well separated and the concentrations of the five metabolites, AFMU, 1U, 1X, 17U, and 17X, were determined. The recoveries of the five metabolites were above 87%, the inter- and intra-day variations were less than 3%. The concentrations of the five metabolites in 120 volunteers were determined. The ratios of the metabolites were employed for the assessment of CYP1A2, NAT, and XO enzymes successfully.

[Determination of caffeine metabolite for the evaluation of N-acetyltransferase, CYP1A2 and xanthine oxidase activities].

Caffeine was used as a metabolic probe to measure, in 120 healthy volunteers, the activities of three enzymes, deduced to be N-acetyltransferase(NAT2), CYP1A2 and xanthine oxidase (XO). The caffeine metabolites of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine(1X), 1-methyluric acid(1U), 1, 7-dimethylxanthine(17X), and 1, 7-dimethyluric acid(17U) in urine were determined with HPLC after 4-5 hours of caffeine drink. The ratios of AFMU/1X or AFMU/(AFMU + 1X + 1U), (AFMU + 1X + 1U)/17X or (AFMU + 1X + 1U)/17U, and 1U/1X or 1U/(1X + 1U) were used as the index of NAT2, CYP1A2, and XO activities respectively. Frequency distribution analysis of the metabolic ratios of NAT2 indicated two distinct group with 20 slow acetylators and 100 rapid acetylators. Similar CYP1A2 activity was found in Chinese compared with European volunteers. Frequency analysis of CYP1A2 indicated the log normal distribution in 120 Chinese. The CYP1A2 index was much higher in smokers than that in nonsmokers. But no obvious difference was observed between young and old volunteers. The XO index also showed log normal distribution and has the similar value compared with European volunteers. The concentration variations of 1X and 1U in young volunteers were much lower than that in old volunteers.

[Evaluation of population pharmacokinetics of cyclosporin A in renal transplantation patients with NONMEM].

NONMEM program was applied for estimating population pharmacokinetic parameters of cyclosporin A (CsA). The influence of body weight, age, sex and drug administration history on clearance were investigated. There were 281 CsA concentrations in whole blood from 60 clinical renal transplantation patients. Samples were analysed by HPLC and FPIA (TDx, Abbott, monoclonal antibody). One compartment open model with first-order absorption and elimination was used to analyse the data. Population mean values of CL(L.h-1), Vd(L), and Ka(h-1) were 59.8, 227, and 1.28 respectively. The interindividual variations of CL, Vd, and Ka were 30.27%, 29.01%, and 75.10% respectively. The residual error was 31.19%. The adjustment value of weight to clearance was 0.03 times with additional model. CL increased 4.31 in male patients, and decreased 12.7 when patients were treated with CsA for a long time.

Pharmacokinetics of ofloxacin through three administration routes.

This paper reports the pharmacokinetic characteristics of ofloxacin (Ofl) through 3 administration routes in 42 patients with respiratory tract infections. The concentration-time data were fitted with a two-compartment model for infusion (inf) and im, and a one-compartment model for po. The pharmacokinetic parameters of Ofl through inf, im and po were: T1/2 beta or T1/2K 6.0 +/- 1.3, 5.0 +/- 1.0, and 5.0 +/- 0.7 h; Vc or Vd 58 +/- 16, 68 +/- 27 and 94 +/- 25 L; Cmax 3.9 +/- 1.0, 2.8 +/- 0.9, and 1.9 +/- 0.7 micrograms.ml-1; AUC 16 +/- 5, 15 +/- 4, and 15 +/- 4 h.micrograms.ml-1; Cl 13 +/- 4, 14 +/- 4, and 14 +/- 3 L.h-1, respectively.

Application of NONMEM method for evaluation of relative biological availability of ofloxacin.

The nonlinear mixed effect model (NONMEM) method for analysis of population pharmacokinetics, was applied to evaluate the relative biological availability of 2 ofloxacin (Ofl) products. The data of randomized crossover study of 2 kinds of Ofl tablets in 12 healthy volunteers were analyzed by NONMEM, as well as standard approach. The relative biological availability evaluated by NONMEM (F = 97.3 +/- 5.0%) was close to that by standard approach (F = 98.2 +/- 3.6%). NONMEM was also valid in accurately evaluating the relative biological availability using sparse clinical data (F = 91.7 +/- 8.0%) which could not be analyzed by standard approach. Thus, the usefulness and advantages of NONMEM were ascertained for the evaluation of biological availability using observational or experimental data.

[Oral cyclosporine pharmacokinetics in renal transplantation patients].

Cyclosporine was extracted from whole blood and analyzed by HPLC. The pharmacokinetics of oral cyclosporine were studied in patients with renal transplant. They were 5 women and 3 men between the ages of 29-49 years. Cyclosporine was used for 47 days to 11 months after renal transplantation. The mean dose was 8.26 +/- 1.41 mg/kg.d (5.88-10.0 mg/kg.d), once each 12 hours. Three hundreds whole blood samples were monitored. The peak concentration (Cmax) was 664.9 +/- 87.5 ng/ml; peak time was 3.27 +/- 1.07 h; slow elimination phase t1/2 beta was 13.53 (6.13-43.3) h.