The bioavailability of a generic diclofenac sodium sustained release tablet preparation (Zolterol, SR) was compared with the innovator product, Voltaren, SR. Twelve healthy adult male volunteers participated in the study, which was conducted according to a randomized, two-way crossover design with a wash out period of one week. The bioavailability of diclofenac was compared using the parameters area under the plasma concentration-time curve (AUC(0-infinity)), peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed for both logarithmically transformed AUC(0-infinity), Cmax values and Tmax value of the two preparations.
Clinical data (n = 275) collected from 52 patients with respiratory tract infection receiving amikacin (AMK) by intravenous infusion were analysed with NONMEM, a computer program designed for estimating population pharmacokinetic parameters. Concentrations of AMK in serum were determined by fluorescence polarization immunoassay (FPIA). A two compartment open model was used for analysing AMK population pharmacokinetics. The influence of body weight (BW), creatinine clearance (CC), administration history (HIS) and state of pathology (chronic obstructional pulmonary disease, COPD) on pharmacokinetics was investigated. The pharmacokinetic parameters of AMK were shown to be influenced by creatinine clearance (CC) and COPD.
To study the genetic basis of N-acetylatransferase polymorphism in Chinese.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.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.The lower frequency of mutant M1 allele compared with that of Caucasians explains the low frequency of slow acylators in Chinese.
OBJECTIVE: The pharmacokinetic profiles and the bioavailability of domestic tablets of bezafibrate were studied in 20 healthy volunteers. METHODS. A single oral dose of 200mg bezafibrate domestic or imported tablet was given to each volunteer according to a crossover design. The concentrations in plasma were measured by HPLC. RESULTS. The results showed that the plasma concentration-time curves of the domestic and imported products were fitted to one-compartment model. The main pharmacokinetic parameters of bezafibrate were:AUC0 - 12 20.32 ±3.98 mg·L-1 and 19.80 ± 3.65 mg·h· L-1, Tmax 2.38 ± 0.89 h and 2.16 ± 0.79 h, Cmax 6.22 ± 1.30 mg·L-1 and 6.57 ± 1.23 mg·L-1; T1/2 1.67 ± 0.43h and 1.49 ± 0.35h for domestic and imported tablet respectively. The pharmacokinetic parameters obtained from our studies showed no significant difference between domestic and imported tablets (P0.05). CONCLUSION: The relative bioavailability of two products was 102.6 ± 8.3 %. The results showed that both formulations were bioequivalent.
Abstract Caffeine metabolism via the 3-demethylation pathway is sequentially catalyzed by the enzymes cytochrome P4501A2 (CYP1A2), xanthine oxidase (XO) and N-acetyltransferase (NAT2). The activities of the three enzymes can be estimated from urinary metabolic ratios of five caffeine metabolites, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1MX), 1-methyluric acid (1MU), 1,7-dimethylxanthine (1,7DMX), and 1,7-dimethyluric acid (17DMU), after the ingestion of caffeine. A HPLC method for simultaneous determination of the five metabolites in human urine was developed, with all the thirteen metabolites of caffeine having good separation. The recoveries of the five metabolites were all above 87.5%, and the interday and intraday coefficients of variation were less than 3%. The method was employed successfully in a population study of 120 healthy volunteers for the assessment of CYP1A2, NAT2, and XO enzymes.
[3H]Kakuol given intragastrically was rapidly absorbed from gut of mice and rats. It was rapidly taken up by various organs,and has a strong affinity for tissues. The highest radioactivity was found in liver(12.1 time as much as in plasma), followed by heart, spleen, pancreas, kidney, lung and brain. The radioactivity in organs disappeared slowly. In 21 d, cumulative excretion of radioactivity was 92.8% of the total dose in urine and 1.2% in feces. The results measured by TLC autoradiography and liquid scintillation counting in urine indicated that[3H] kakuol was excreted mainly in urine in unchanged form. The rate of binding with plasma protein was 39%. After iv in mice, the decline of radioactivity in the plasma showed a biphasic curve. Pharmacokinetic parameters:t(1/2 alpha)=0.21 h, t(1/2 beta)=40 h, Vc=2.3 L/kg, Vd=26.5 L/kg.
Terbinafine is an orally active allyamine antifungal agent that has been newly marketed in China. Abdel-Rahman et al. [1] showed that terbinafine was an inhibitor of CYP2D6 activity and as potent as quinidine in vitro. A subsequent in vivo study confirmed that terbinafine inhibited CYP2D6 activity sufficiently to produce a discordance between genotype and phenotype for this polymorphically expressed enzyme [2]. There was also a case report of nortriptyline intoxication in a patient also taking terbinafine [3]. The genetic polymorphism of CYP2D6 in Chinese differs from that in Caucasians because of the lower prevelance (1%) of poor metabolizers (PM) in the former [4] compared with the latter (5–10%) [5]. The aim of the present study was to determine whether terbinafine inhibits CYP2D6-mediated metabolism in Chinese to the same extent as in Caucasians. Ten (five men and five women) native Chinese subjects were recruited with a mean age was 24 ± 5 years and a mean weight of 60 ± 12 kg. All were healthy as assessed by blood biochemistry and none smoked tobacco or drank alcohol. Subjects were excluded if they were receiving any medications known to induce or inhibit cytochrome P450. Informed consent was obtained from all subjects. All subjects were genotyped to detect wild type CYP2D6 (CYP2D6*1) and the allele possessing the point mutation (C188→T, CYP2D6*10) causing diminished CYP2D6 activity according to a method described previously [6]. Evaluation of CYP2D6 activities at baseline and after terbinafine therapy was performed according to a dextromethorphan phenotyping method [4]. Terbinafine hydrochloride tablets (250 mg) were administered once daily to all subjects for 14 days. The concentrations of dextromethorphan and dextrophan in urine were measured by a reverse-phase h.p.l.c. method with fluorescence detection developed in our laboratory [7]. Subjects' urinary molar metabolic ratio (MR) was calculated according to the method of Schmid [8]. Subjects with a MR > 0.3 were categorized as poor metabolizers (PM), and those with a MR ≤ 0.3 as extensive metabolizers (EM). Differences in the dextromethorphan MR and urinary recovery before and after pretreatment with terbenafine were tested by using a Student's t-test for paired samples. A P value of less than 0.05 was regarded as statistically significant. 95% confidence interval (95% CI) for differences in means were also calculated. Data are reported as mean±s.e. mean. For 10 subjects treated with terbinafine for 14 days, mean MR values were increased from 0.028 ± 0.027–0.321 ± 0.333 (difference: 0.293, 95% CI: 0.072,0.514, P = 0.015) with a mean of 15.6 fold increase. Four out of 10 EM subjects were converted to apparent PMs with respect to CYP2D6 (Table 1), indicating a strong inhibitory effect of terbinafine on dextromethorphan metabolism. For CYP2D6 C188/C188, dextromethorphan MR values increased from 0.004 ± 0.001 at baseline to 0.113 ± 0.030 after terbinafine treatment, a 32-fold increment. For CYP2D6 C188/T188 and T188/T188, there was about a 10-fold increase in dextromethorphan MR. Abdel-Rahman et al.[2] showed that a mean 97-fold increase in the dextomethorphan MR was observed for six Caucasian extensive metabolizers after 2 weeks' treatment with terbenafine. For 10 Chinese extensive metabolizers at the same daily dose as in our study the mean fold increase in dextromethorphan MR was six times less. The CYP2D6 alleles associated with poor metabolizers in Caucasians are mainly CYP2D6*3 and CYP2D6*4 (> 98%) [9]. However, these alleles are much less frequent (< 10%) in Chinese [10]. On the other hand, CYP2D6*10B, a gene copy with a C188→T mutation, is predominant in Chinese extensive metabolizers [6] and is associated with decreased CYP2D6 activity. We have found that the mean baseline MR values in the 10 Chinese EM subjects from the present study were about five times as high as that in the six Caucasian EM subjects reported by Abdel-Rahman [2] (0.028 ± 0.027 vs 0.006 ± 0.003). Noticeably, there was no significant difference in mean dextromethorphan MR values between the two groups after terbinafine therapy (0.321 ± 0.333 vs 0.282 ± 0.076, P > 0.05). Therefore, it is not unexpected that the increase in dextromethorphan MR in Chinese is not as high as that in Caucasians after the same terbinafine dose and duration of treatment.
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.
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