Relative bioavailability of three cefixime formulations

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".     

The bioequivalence study of folifer-Z: a new formulation of sustained-release iron and zinc

The bioequivalence of Folifer-Z tablets, a new sustained-release iron and zinc formulation was evaluated and compared to that of Fefol-Z capsules in 30 healthy male subjects. Each subject received a single oral dose of either product according to a randomized two-way crossover design. A washout period of 1 week was allowed after each treatment. Blood samples were obtained over a 24-h period, and iron and zinc concentrations were measured. The pharmacokinetic parameters of Folifer-Z were Cmax (103 +/- 46.2 micrograms/dl), Tmax (5.93 +/- 2.94 h) and AUC0-24 h (1937 +/- 706 micrograms/dl per h), whereas the corresponding Fefol-Z values were Cmax (109 +/- 41.5 micrograms/dl), Tmax (6.64 +/- 2.54) and AUC0-24 h (1865 +/- 699 micrograms/h per dl). Analysis of variance on log-transformed data for Cmax and AUC0-24 h revealed lack of significant differences among the two formulations. The mean relative bioavailability of AUCtest/AUCreference was 1.07 (90% confidence interval range: 99-115%) and for Cmax test/Cmax reference was 0.96 (90% confidence interval range: 88-105%). Regarding the zinc results, the pharmacokinetic parameters of Folifer-Z values were Cmax (101 +/- 20.7 micrograms/dl), Tmax (4.86 +/- 1.53 h) and AUC0-24 h (1944 +/- 202 micrograms/h per dl), while the corresponding Fefol-Z values were Cmax (102 +/- 20.7), Tmax (4.93 +/- 1.51) and AUC0-24 h (1953 +/- 200). Analysis of variance on log-transformed zinc data for Cmax, Tmax and AUC0-24 h revealed lack of significant difference among the two formulations. The mean relative bioavailability of AUCtest/AUCreference was 0.98 (90% confidence interval range; 95-101%) and for Cmax test/Cmax reference was 0.92 (90% confidence interval range: 89-96%). The results also indicate a possible inhibition of zinc absorption by iron content of both formulations. It is concluded that Folifer-Z product is bioequivalent to Fefol-Z product.     

Comparison of gastroretentive microspheres and sustained-release preparations using theophylline pharmacokinetics

The objective of this study was to use the pharmacokinetics of theophylline to compare various gastroretentive microspheres. Three types of theophylline microspheres prepared from a hydrophobic dextran derivative were characterized in terms of drug release in-vitro and floating and mucoadhesive properties. Theophylline pharmacokinetic studies were conducted in Beagle dogs, comparing bulk powder, commercial sustained-release granules (Theodur), sustained-release microspheres, floatable microspheres and mucoadhesive microspheres. Theodur and sustained-release microspheres resulted in a lower maximum concentration (Cmax) (P < 0.01) and larger values for mean residence time (MRT) (P < 0.05) than bulk powder, whereas area under the concentraion-time curve (AUC) were lower. The floatable microspheres showed a larger value for MRT than bulk powder (P < 0.01), and a larger AUC than Theodur (P < 0.05). The pharmacokinetic parameters of the mucoadhesive microspheres indicated an increase in AUC without decreasing the rate of bioavailability. Overall, the gastroretentive microspheres improved the extent of bioavailability of theophylline, which is absorbable from the entire gastrointestinal tract. The mucoadhesive microsphere showed a prolonged serum drug level, indicating a superior sustained-release delivery system for theophylline.     

Pharmacokinetics and bioavailability of acyclovir sustained-release tablets in dogs.

The pharmacokinetics and bioavailability of acyclovir sustained-release tablets in dogs were investigated. Blood concentrations of acyclovir were determined by RP-HPLC after a single oral dose of two kinds of acyclovir tablets given separately to 6 beagle dogs. The main pharmacokinetics parameters of the acyclovir sustained-release tablet were as follows: T1/2, Tmax and Cmax were 4.10 +/- 0.20 h, 4.05 +/- 0.54 h and 6.90 +/- 0.68 [microg x ml(-1), respectively. MRT was 9.02 +/- 0.44 h. Using acyclovir standard tablet as control, relative bioavailability of the acyclovir sustained-release tablet was 152.2 +/- 49.90%. According to the two-tailed t-test, there was a distinct difference in the data for Tmax, Cmax and AUC between acyclovir sustained-release tablets and acyclovir standard tablets, and the absorbability of acyclovir sustained-release tablets was much better than that of the acyclovir standard tablets.     

茶碱在正常及肝纤维化大鼠体内的药物动力学

目的比较茶碱在正常及肝纤维化大鼠体内的药物动力学。方法 SD大鼠24只,分成4组:静脉给药正常组、静脉给药模型组、口服给药正常组和口服给药模型组,每组各6只,采用尾静脉注射或灌胃方式给予茶碱5mg/kg,用HPLC法测定茶碱血药浓度,运用DAS2.1.1拟合药动学参数,并采用SPSS13.0软件进行统计分析。结果在口服和静脉给药条件下,茶碱的药动学参数AUC0-24h、AUC0-∞、CLz(或CLz/F)、MRT0-24h、MRT0-∞和t1/2z在正常鼠和肝纤维化鼠之间差异有统计学意义(P<0.05),Cmax,tmax,Vz(或Vz/F)的差异则无统计学意义。结论茶碱在大鼠体内的药动学会受肝纤维化显著影响。     

Bioavailability of vinpocetine and interference of the time of application with food intake.

In a pilot study based on an open cross-over design involving four phases, the relative bioavailability of the eburnamenine derivative vinpocetine (CAS 42971-09-5) was investigated in 8 healthy volunteers in relation to different times of drug administration relative to food intake. The substance was applied orally as 10 mg film tablets. The areas under the plasma concentration-time curves (AUC) amounted to 27.3 +/- 18.1 ng.h/ml (fasting) and 42.8 +/- 27.4 up to 54.3 +/- 38.4 ng.h/ml (non-fasting, intake before and after meal, resp.). The relative bioavailability under non-fasting conditions was found to be approx. 60 to 100% higher than under fasting conditions.     

Usefulness and safety of theophylline injection form (Theodrip) for the treatment of acute asthma

The effects of the speed of intravenous infusion on the pharmacokinetics of theophylline were studied in 9 healthy volunteers (Ex I). Subjects were intravenously administered either six 4.8 mg/kg theophylline (Theodrip, Nikken Chemicals Co., Ltd., Japan) or three matching placebo injections (4.8 ml/kg physiological saline) for 30 min (Step I) or for 15 min (Step II). In Steps I and II, Cmax was 10.8 +/- 1.1 and 10.8 +/- 0.8 micrograms/ml, respectively. These Cmaxs were concentrations yielding therapeutic effects in patients with acute asthma. Next, comparative pharmacokinetics between theophylline (Theodrip) and aminophylline were examined by a crossover method in 16 healthy volunteers (Ex II). The 90% confidence limits of the differences of mean values were within 80-120% and were 92.8-100.1% for Cmax, 99.7-105.3% for t1/2 and 100.2-104.4% for AUC. Thus, we concluded that the pharmacokinetics of the plasma theophylline after intravenous administration of Theodrip (theophylline at 4.8 mg/kg) were bioequivalent to those of aminophylline (6.0 mg/kg) for 30 min. In Ex I and II, no subjects had adverse effects and in Ex I no influence on ECG was seen. In addition, the convenience of Theodrip was compared with that of ampules of aminophylline among nurse volunteers (Ex III). The times required for set-up of Theodrip were significantly shorter than those of aminophylline ampules. On the other hand, the adverse reactions to aminophylline resulting from hypersensitivity reactions to its ethylenediamine component have been reported. Theodrip consists of 200 mg theophylline and 200 ml physiological saline in a plastic bag. Therefore, Theodrip, which does not contain ethylenediamine, is expected to have less adverse effects and be easier to handle than aminophylline.     

Bioequivalence study of two losartan formulations administered orally in healthy male volunteers

The bioavailability of a new losartan preparation (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, CAS 114798-26-4) was compared with the reference preparation of the drug in 24 healthy male volunteers, aged between 19 and 32. The open, randomized, single-blind two-sequence, two-period crossover study design was performed. Under fasting conditions, each subject received a single oral dose of 100 mg losartan as a test or reference formulation. The plasma concentrations of losartan and its active metabolite were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-36h, AUC0-infinity, Cmax, t1/2, and Ke. Values of AUC0-infinity demonstrate nearly identical bioavailability of losartan from the examined formulations. The AUC0-infinity of losartan was 2019.92+/-1002.90 and 2028.58+/-837.45 ng x h/ml for the test and reference formulation, respectively. The AUC0-infinity of the metabolite was 10851.52+/-4438.66 and 11041.18 +/-5015.81 ng x h/ml for test and reference formulation, respectively. The maximum plasma concentration (Cmax) of losartan was 745.94+/-419.75 ng/ml for the test and 745.74+/-329.99 ng/ml for the reference product and the Cmax of the metabolite was 1805.77+/-765.39 and 1606.22 +/-977.22 ng/ml for the test and reference product, respectively. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for both losartan and its active metabolite. 90 % confidence limits calculated for Cmax and AUC from zero to infinity (AUC0-infinity) of losartan and its metabolite were included in the bioequivalence range (0.8-1.25 for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for losartan and its main active metabolite.     

Comparative biological availability of two different ibuprofen granules]

Bioavailability of ibuprofen (CAS 15687-27-1) was investigated in 12 healthy volunteers who received 2 sachets of newly developed effervescent granules (Imbun), each containing 500 mg of ibuprofen lysine salt (corresponding to 292.6 mg of ibuprofen) as the test preparation and 1 sachet of commercially available granules containing 600 mg ibuprofen. Blood samples were withdrawn pre-dose and at 16 occasions until 10 h post dose. Ibuprofen plasma concentrations were assayed by HPLC using a proprietary column-switching technique. Maximum plasma concentrations, Cmax, and times of their occurrence, tmax, were taken from the plasma data directly, areas under the plasma level/time curves, AUC0-10, were calculated using the trapezoidal rule. Pharmacokinetic parameters were checked for significant differences using ANOVA with p = 0.05. When the test preparation was applied maximum ibuprofen levels of 60 +/- 17 micrograms/ml were reached at 27 +/- 17 min p. appl. while Cmax was 52 +/- 12 micrograms/ml at tmax = 94 +/- 27 min after application of the reference preparation. AUC values were 150 +/- 44 microgramsh/ml (test) and 148 +/- 33 microgramsh/ml (reference), respectively. Thus, relative bioavailability of ibuprofen was 101.8 +/- 16.3% (or 104.1 +/- 16.7% when the slight differences in doses were corrected for). Differences in extent of absorption as measured by AUC and Cmax proved to be insignificant whereas differences in absorption rate as measured by tmax were highly significant (p < 0.001).     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

Pharmacokinetic study of theophylline in dogs after intravenous administration with and without ethylenediamine

Aminophylline (ethylenediamine salt of theophylline) and Theodrip, a new formulation of theophylline developed by Nikken Chemicals, are drugs for the treatment of acute bronchial asthma in injectable form. The present study was conducted using dogs to first confirm the bioequivalence of the two injectable forms containing theophylline and aminophylline and to secondly clarify the influence of the rate of venous infusion on the pharmacokinetics of theophylline in plasma. The following results were obtained: 1) Pharmacokinetic parameters of plasma theophylline after an intravenous bolus injection were close to those after the dosing of aminophylline in dogs by a crossover method. Thus, the 95% confidence limits of mean value differences of Cmax, t1/2 and AUC between the two injection forms were in the range of -3.16-4.28%, -6.19-7.28% and -7.23-5.28%, respectively. These results indicate the bioequivalence between theophylline and aminophylline in dogs from a pharmacokinetic point of view as well as the lack of influence of ethylenediamine on the pharmacokinetics of theophylline. 2) After the intravenous bolus injection (30 sec) and the 15-min constant rate infusion of theophylline to dogs, the plasma concentrations of theophylline were 27.37 +/- 3.67 micrograms/ml and 18.34 +/- 2.32 micrograms/ml immediately after the completion of administration, respectively. It is notable that in humans the former concentration level has been observed to frequently cause adverse effects, whereas the latter was in the safe range. Consequently, the 15-min constant rate infusion did not result in the rapid increase in the plasma theophylline concentrations and was superior to the bolus injection from the viewpoint of maintaining the safety plasma concentrations. In conclusion, to avoid hypersensitivity due to ethylenediamine and the adverse effects caused by high plasma concentrations of theophylline, it was considered that constant rate infusion of theophylline to the venous is preferable in the clinical setting.     

5—单硝酸异山梨醇酯缓解胶囊在中国健康男青年的药物动力学

AIM: To compare the pharmacokinetics of domestic and imported sustained-release capsule of 5-isosorbide mononitrate (5-IM). METHODS: A single and 5-d-repeated oral doses of 5-IM 50 mg were performed on 2 groups of 20 Chinese healthy subjects (10 subjects for each group) in a randomized crossover protocol. The 5-IM in plasma were measured by gas chromatography with electron-captured detector method. Data were analyzed automatically by using a CAPP program on a PC computer. RESULTS: Fitting the 5-IM concentration-time curves to one-compartment model or following trapezoidal rule, the parameters such as Tmax, Cmax, Ke, MRT, and AUC were calculated and there were no significant differences between the two kinds of capsule. The major pharmacokinetic parameters of domestic and imported 5-IM sustained-release capsule with a 5-d multiple dose were respectively: Cmax (677 +/- 103) and (702 +/- 76) micrograms.L-1; Tmax (5.1 +/- 2.0) and (5.6 +/- 1.3) h; MRT (11.5 +/- 0.5) and (11.4 +/- 0.7) h; AUC0-infinity (12,121 +/- 1346) and (12,352 +/- 988) micrograms.h.L-1. The fraction of drug absorbed in vivo was correlated well with the percentage amount of drug released in vitro at corresponding time (P < 0.05), and the fluctuation indices on d 5 in multiple dose study were not significantly different between the two formulations (P > 0.05). The relative bioavailability of the domestic capsule for single and multiple dose were 96% +/- 11% and 98% +/- 10%, respectively. CONCLUSION: Domestic 5-IM sustained-release capsule showed bioequivalence compared with the imported capsule and provided the same nitrate-low interval in the latter part of the 24-h dosing interval.     

Investigation of diurnal changes in the disposition of theophylline

The mechanism of observed temporal variations in plasma theophylline concentrations has been investigated. Eight healthy volunteers were given both oral and intravenous doses of theophylline (5 mg/kg) at 09.00 h and 21.00 h under controlled conditions. Regular plasma concentration measurements were made following each dose in order to determine the diurnal and nocturnal disposition of the drug. Plasma theophylline concentrations at 0.5 h following each oral dose were 6.9 +/- 0.8 micrograms/ml, a.m., and 3.9 +/- 0.6 microgram/ml, p.m. (P less than 0.05). Time to peak concentration was 1.69 +/- 0.28 h, a.m.; 2.13 +/- 0.23 h, p.m. (P less than 0.05). Values for ka were not significantly different, however. Overall bioavailability, volume of distribution and systemic clearances, calculated for the 12 h period after each dose, did not differ significantly between day and night. Diurnal variations in theophylline disposition do not appear to be the result of changes in metabolism or excretion, but may reflect minor differences in absorption.     

The bioequivalence of two nifedipine fluid capsules

Bioequivalence of Two Nifedipine Liquid Capsules Plasma concentration-time profiles of nifedipine were determined in an open, randomised cross-over study on 12 healthy volunteers after application of 10 mg nifedipine as two different soft gelatin capsule preparations. In vitro dissolution tests showed a significant difference between the reference preparation (R) and the generic preparation (P). Maximal nifedipine plasma concentrations (Cmax) measured at tmax (0.6 h, median) for P averaged 87.5 +/- 32.7 micrograms/l, corresponding values for R were 95.4 +/- 41.1 micrograms/l and 0.46 h. Differences in Cmax and tmax values were not statistically significant. Mean areas under the curves AUC(0-10 h) were 128.7 +/- 59.9 micrograms.h/h after p and 123.3 +/- 49.3 micrograms.h/l after R (n.s.). 95% confidence intervals for indices of bioavailability based on AUC and Cmax overlapped, indicating that the two preparations are bioequivalent.     

Evaluation of tetracycline on theophylline disposition in patients with chronic obstructive airways disease

Theophylline is a commonly used bronchodilator in the treatment of chronic obstructive airways disease (COAD) with a narrow therapeutic range of 10 to 20 micrograms/ml. Patients with COAD frequently receive concomitant antibiotic therapy for respiratory infections. This study evaluated the effect of tetracycline therapy on theophylline disposition in adults with COAD. Six males (five nonsmokers) with obstructive ventilatory defects were studied in two phases: control, after receiving sustained-release theophylline in the same dosage regimen for four days, and treatment, after receiving tetracycline 250 mg po qid for five days in addition to theophylline. During each phase, 10 blood samples were obtained over one dosing interval and analyzed for theophylline content. The following pharmacokinetic parameters were calculated: Cmin, Cmax, Css, percentage fluctuation and Cl. Differences for each value were tested as paired data with Student's two-tailed t-test. When all patients were evaluated, the only statistically significant difference was for Cmax. However, when the five nonsmokers were evaluated separately, differences were observed for Css (micrograms/ml; mean +/- SD) 9.3 +/- 3.0, control, and 10.6 +/- 3.8, treatment (p = 0.041); and for Cl [( ml/h]/kg; mean +/- SD) 49.0 +/- 11.1, control, and 43.6 +/- 10.2, treatment (p = 0.019). This study demonstrates that tetracycline may weakly inhibit theophylline clearance in nonsmoking adults with COAD.     

Influence of food on the absorption of theophylline administered in the form of sustained release tablet and microgranules

Two sustained-release formulations of theophylline, tablets (T) and microgranules (MG) forms, were administered in a randomized order to 8 healthy subjects in fasting or with a high-protein test meal (50 per cent). Blood was collected for 32h post-dose. In fasting subjects, absorption of theophylline was significantly faster for T (tmax 5 h) as compared with MG (tmax 8 h, p less than 0.05), but Cmax and AUC were comparable; intersubject variability was higher with T. Administration of a high-protein test meal with T produced a significant decrease of the zero-order absorption rate constant of theophylline (K omicron 37.8 +/- 9.1 mgh-1 after meal versus 58.8 +/- 13 mgh-1 in fasting, p = 0.01), tmax was doubled to 10 h, and Cmax increased by 25 per cent (6.33 +/- 2.16 mgl-1 versus 5.04 +/- 1.28 mgl-1, p less than 0.02); with MG, tmax were the same (8 h), Cmax were not significantly increased (4.79 +/- 0.84 mgl-1 versus 4.55 +/- 0.67 mgl-1), absorption was delayed (lag-time 1.28 +/- 0.58 h) and the absorption was slightly accelerated (K omicron 50.4 +/- 10.4 mgh-1 versus 42.3 +/- 11.9 mgh-1, NS). For each form bioavailability was not significantly modified by food. This study demonstrated that food rich in protein modifies the absorption rate of theophylline in a sustained-release tablet formulation but is without influence in a pH-independent, sustained-release microgranule formulation.     

Bioequivalence study of two amoxicillin formulations

A randomized single-dose crossover study was conducted in 24 healthy male volunteers to compare the bioavailability of two amoxicillin (CAS 26787-78-0) formulations, Glomox tablet (test) and a commercially available original preparation, amoxicillin capsule (reference). One thousand milligram of each formulation were administered after an overnight fast with a washout period of three days. Sixteen blood samples were collected over 10 h, amoxicillin concentrations in deproteinized serum were determined by a high performance liquid chromatographic (HPLC) assay, and pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the curve (AUC0-->t and AUC0-->infinity), and elimination half-life (t1/2) were 13.30 +/- 4.52 and 12.99 +/- 3.56 microg/ml, 1.92 +/- 0.76 and 2.02 +/- 0.62 h, 42.50 +/- 13.62 and 42.24 +/- 12.35 microg x h/ml, 46.31 +/- 13.23 and 46.08 +/- 12.14 microg x h/ml, and 1.54 +/- 0.39 and 1.48 +/- 0.48 h for the test and reference formulation, respectively. The parametric 90 % confidence intervals of the mean of the difference (test-reference) between log-transformed values of the two formulations were 92.61% to 109.50%, 92.83% to 109.12%, and 93.11% to 109.41% for AUC0-->t, AUC0-->infinity, and Cmax, respectively. The results indicate that the two formulations can be considered equivalent with regard to the rate and extent of absorption under fasting conditions.     

Pharmacokinetic studies on oral antibiotics in pediatrics. I. A pharmacokinetic study on cefixime in pediatrics

A pharmacokinetic study on cefixime (CFIX) 5% granules for pediatric use was performed, and pharmacokinetic parameter were calculated. 1. Six school children were administered orally with CFIX granules at a dose level of 3 mg/kg either at 30 minutes before meal or at 30 minutes after meal on a crossover design, and serum concentrations and urinary excretion rates of CFIX were determined. Tmax, Cmax, T 1/2 and urinary excretion rate (0-12 hours) following the administration before meal were 3.33 +/- 0.42 hours, 1.03 +/- 0.17 micrograms/ml, 2.31 +/- 0.26 hours and 15.3 +/- 2.2%, respectively, Tmax, Cmax, T 1/2 and urinary excretion rate following the the administration after meal were 4.00 +/- 0.52 hours, 0.90 +/- 0.09 micrograms/ml, 3.11 +/- 0.21 hours and 11.3 +/- 1.6%, respectively. Earlier Tmax, higher Cmax and higher urinary excretion rate were observed when the drug was administered before meal than when administered after meal. These differences between the 2 groups were not statistically significant. 2. Five school children were administered orally with CFIX granules at 30 minutes after meal at a dose level of either 3 mg/kg or 6 mg/kg on a crossover design, and serum concentrations and urinary excretion rates of CFIX were determined. Cmax and AUC at a dose level of 3 mg/kg were 1.01 +/- 0.26 mg/ml and 5.86 +/- 1.13 micrograms.hr/ml, respectively, and Cmax and AUC at a dose level of 6 mg/kg were 1.76 +/- 0.29 micrograms/ml, 12.54 +/- 1.77 micrograms.hr/ml, respectively. A dose response relationship was thus observed. Seven infants (3 mg/kg) and 3 infants (6 mg/kg) were administered orally with CFIX granules at 30 minutes after meal. Cmax and AUC at a dose level of 3 mg/kg were 2.45 +/- 0.26 micrograms/ml, 33.50 +/- 7.62 micrograms.hr/ml, respectively, and Cmax and AUC at a dose level of 6 mg/kg were 4.42 +/- 0.98 micrograms/ml, 66.85 +/- 25.19 micrograms.hr/ml, respectively. A dose response was observed. 3. Eleven school children, 5 younger children and 7 infants were administered orally with CFIX granules at a dose level of 3 mg/kg at 30 minutes after meal, and serum concentrations and urinary excretion rates of CFIX were determined. Tmax in school children, younger children and infants were 3.82 +/- 0.33 hours, 5.20 +/- 0.49 hours and 5.43 +/- 0.37 hours, respectively. Earlier Tmax's were observed in school children than in other children. Cmax in school children, younger children and infants were 0.95 +/- 0.12 micrograms/ml, 0.56 +/- 0.06 micrograms/ml and 2.45 +/- 0.26 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Bioequivalence assessment of two capsule formulations of omeprazole in healthy volunteers

A randomized, single-dose, crossover study was conducted to assess the bioavailability of two omeprazole (CAS 73590-58-6) capsule formulations, Emilok (test) and a commercially available original preparation (reference), under fasting conditions. A 20 mg dose of each formulation was administered to 36 healthy male volunteers with one-week washout period, 17 blood samples were collected over 12 h, plasma omeprazole concentrations were determined by a locally validated high performance liquid chromatography (HPLC) assay, and omeprazole pharmacokinetic parameters were analyzed by the standard non-compartmental method. Mean +/- SD of Cmax, Tmax, AUC(0 --> t), AUC(0 --> infinity), and t1/2 were 0.41 +/- 0.21 and 0.48 +/- 0.27 microg/ml, 1.98 +/- 1.02 and 1.63 +/- 0.78 h, 0.95 +/- 0.78 and 1.00 +/- 0.90 microg x h/ml, 0.99 +/- 0.81 and 1.04 +/- 0.95 microg x h/ml, and 1.30 +/- 0.64 and 1.14 +/- 0.61 h for the test and reference formulations, respectively. The parametric 90% confidence intervals on mean difference between log-transformed values of the two formulations were within the acceptable bioequivalence range of 80% to 125% for AUC(0 --> t) and AUC(0 --> infinity) (88.63% to 104.98%, and 91.71% to 106.86%, respectively) but not for Cmax (76.27% to 103.63%). ANOVA revealed significant subject's effect for AUC(0 --> t), AUC(0 --> infinity), Cmax, and t1/2 with a ratio of the inter-subject to intra-subject coefficient of variation of 3.66, 3.92, 1.25, and 1.46, respectively. The results confirm the presence of marked individual variations in the pharmacokinetics of omeprazole and indicate that the two formulations are equivalent in relation to the extent but not the rate of absorption.     

Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs

The single-dose pharmacokinetics and bioavailability of three ketoconazole formulations were evaluated using HPLC in five healthy human volunteers and six male mongrel dogs. The human volunteers received 400 mg po of ketoconazole as tablet (Ktab) and solution (Ksol) formulations. The dogs received 400 mg po of Ktab and Ksol, and 376 mg iv of an intravenous dose (Kiv). In humans the AUC value for Ksol (62.21 +/- 21.2 microgram X h/ml; mean +/- SD) was significantly greater than for Ktab (50.0 +/- 15.2 micrograms X h/ml; p less than 0.05). Peak serum concentrations (Cmax), time to peak serum concentrations (tmax), t1/2, and the terminal elimination rate constant (kel) did not differ between Ktab and Ksol. This suggests that the administration of Ksol may be a useful alternative to dosage increases in situations where low bioavailability of ketoconazole in tablet form is suspected. The mean systemic clearance (CLs) of Kiv in dogs was 2.74 +/- 1.10 mL/min/kg, the volume of distribution at steady state (Vdss) was 0.72 +/- 0.28 L/kg, and the half-life was 2.7 +/- 1.6 h. Considerable variability was seen in the AUC of ketoconazole, particularly with the oral preparations. The absolute bioavailability of Ktab was 0.50 +/- 0.38, which did not differ statistically from that of Ksol, 0.56 +/- 0.23. The Ksol showed less variability in AUC, Cmax, and F values than did Ktab, and two dogs with low bioavailability with Ktab (0.04 and 0.07) had substantially greater bioavailability with Ksol (F = 0.96 and 0.57, respectively). Evaluation of Kiv in dogs confirms decreased bioavailability from orally administered tablet formulations of ketoconazole.