Single dose bioavailability of two different digoxin tablets

In a single dose bioequivalence study in 10 healthy young adults the absorption profiles and bioavailability of two digoxin containing tablets (A = digoxin-Pharbita 0.25 mg and reference drug B) were compared and related to the in vitro dissolution rate of both tablets. Two tablets of each product (= 0.50 mg of digoxin) were taken at random on an empty stomach; two weeks elapsed between the two treatments. Frequent blood sampling was performed up to 24 h after intake of the dose. Digoxin plasma concentrations were measured by means of radioimmunoassay. No significant differences (p greater than 0.05) were found in the mean values of the peak plasma concentration (cmax), time to peak (tmax) and area under the plasma concentration versus time curve for the period of 0-10 h after drug intake (AUC0-10), although in most subjects the absorption process after intake of product A was slightly faster, with slightly higher peak. This might be related to a slightly faster release of digoxin from the product A dosage form, as was seen from the dissolution test data. The relative bioavailability of product A as compared to product B, accounted for 97.7 +/- 28.7% (mean +/- S.D.). These results indicate, that both products can be considered as being bioequivalent.     

Single oral dose pharmacokinetics and comparative bioavailability of danazol in humans.

A comparative bioavailability study was conducted with two capsule formulations of danazol (200 mg) in 16 healthy adult male volunteers. Fasting subjects received single doses (400 mg) of each formulation on separate occasions 1 week apart. Blood samples were drawn at specified times up to 32 h after the dose and danazol concentrations in plasma were determined by a specific and sensitive HPLC method. The results for one subject were excluded as outlier values. The data from the other 15 subjects showed small differences, which did not achieve statistical significance between the formulations with respect to Cmax, Tpeak and AUC0-infinity. The mean elimination half-life for danazol was 9.44 +/- SD 2.74 h and the mean apparent total body clearance was 710 +/- SD 2161 h-1. These data differed from previously published results, probably as a result of the more sensitive and specific assay method used in the present work. It is likely that a high proportion of the oral dose of danazol is eliminated by presystemic metabolism.     

Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers

The results of two randomized, single-dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucleoside antiretroviral drug. In the first study 12 healthy male volunteers received nevirapine 15 mg via short-term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg/200 mL). Following the i.v. dose, nevirapine had a low systemic clearance (Mean +/- S.D., Cl = 1.4 +/- 0.3 L/h) and a prolonged elimination phase (t(1/2beta) = 52.8 +/- 14.8 h; MRT = 81.4 +/- 22.4 h). Nevirapine absolute bioavailability was 93 +/- 9% and 91 +/- 8% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers were administered nevirapine as a 200 mg production-line tablet or oral reference solution (200 mg/200 mL). There was no significant difference in bioavailability between the tablet and reference solution. Overall, comparison of the pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a single dose.     

Single dose absorption profiles and bioavailability of two different salbutamol tablets

In a single dose cross-over experiment in twelve healthy adults a comparison of the absorption profiles and the relative bioavailability was made between a new salbutamol containing tablet (preparation A = Salbutax) and a commercially available and accepted formulation as reference (preparation B), both containing 4 mg salbutamol. Salbutamol plasma concentrations were measured frequently during a period of 16 h post dosing. Maximum salbutamol plasma concentrations after intake of product A and product B on an empty stomach were reached after 2.3 +/- 0.9 (= mean +/- S.D.) and 2.4 +/- 1.1 h, respectively, and accounted for 14.3 +/- 2.5 and 12.8 +/- 2.6 micrograms X l-1, respectively. The differences were not found to be significant (p greater than 0.05). The areas under the plasma concentration-time curves (AUC0----16), as obtained after administration of tablet A and tablet B, accounted for 73.5 +/- 14.0 and 65.0 +/- 11.8 micrograms X l-1 X h, respectively, the difference being marginally significant (p = 0.05). This results in a relative bioavailability of 114.3 +/- 15.7% for the product A 4-mg tablets. It is concluded that both products can be considered as having comparable bioavailability.     

The effect of dose form on the bioavailability of mebendazole in man.

Four different dose forms of mebendazole were administered to human volunteers, and urine was collected and assayed for mebendazole and unconjugated metabolites of mebendazole. Oral administration of mebendazole as an oily suspension slightly enhances the bioavailability of the drug, however mebendazole is not absorbed following rectal administration. The major urinary metabolite of mebendazole in humans is 2-amino-5(6)[alpha-hydroxybenzyl]benzimidazole (IV), not 2-amino-5(6) benzoylbenzimidazole (II), as previously reported.     

Encapsulation of aluminium hydroxide fillers with poly-methyl-methacrylate.

A process was developed for the microencapsulation of inorganic filler particles with poly-methyl-methacrylate, to increase the interaction between the hydrophilic filler particles and a polymer matrix. The filler utilised was aluminium hydroxide with an average diameter of 1.9 microm and a specific surface area of 5 m2/g. The process comprised a surface modification, in which a monolayer of isopropoxy titanium isostearate was chemically bound to the surface to render it hydrophobic and to ensure a chemical bond between the filler and the organic phase. Then, an encapsulation reaction was carried out by means of an emulsion-like polymerization process at monomer starved conditions. The modified particles were stabilized in water with sodium-dodecyl-sulphate. A redox system consisting of cumene-hydroperoxide in combination with sodium-formaldehyde-sulphoxylate and iron(II) salt was applied for the initiation of the polymerization. Besides surface polymer, free polymer particles were also formed. The parameters which varied were the filler concentration, the concentration of the initiator components and the surfactant concentration. At optimum conditions, approximately 50% of the added monomer polymerized at the modified filler surface, thus forming encapsulated filler particles. SEM together with TGA analysis indicated that a smooth polymer layer had been formed on the filler surface. At high filler loading, however, coagulation occurred.     

The influence of particle size on the bioavailability of inhaled temazepam.

1. Temazepam was administered by aerosol using a standard protocol to healthy volunteers. Two studies are reported in which different dosage formulations were used: a) 30 mg of the 5 mu diameter particle (n = 6); b) 10 mg of the 2 mu diameter particle (n = 6). 2. An open crossover design was followed in each study. On one occasion in both studies subjects used a gargling procedure to remove drug which had been deposited in the mouth and oropharynx. 3. Serial venous blood samples were drawn for a period of 24 h. The mean total AUC of the 5 mu preparation was significantly reduced by gargling (3153 ng ml-1 h to 1066 ng ml-1 h) (F = 0.32). Gargling also had a significant effect on the mean AUC(0-1 h). 4. In contrast gargling had no significant effect on the mean AUC associated with the smaller diameter particle preparation (630 ng ml-1 h) vs 397 ng ml-1 h (F = 0.74). 5. These findings also indicate that temazepam deposition in the pulmonary tree is enhanced by the use of a 2 mu rather than a 5 mu diameter particle. However, the plasma drug concentrations achieved are unlikely to produce a sufficiently marked sedative effect for endoscopic investigations such as gastroscopy.     

The influence of polyvinylpyrrolidone on the solution and bioavailability of hydrochlorothiazide.

The dissolution properties of hydrochlorothiazide-PVP 10 000 mechanical mix and coprecipitate systems were qualitatively similar to those previously reported using hydroflumethiazide. Quantitative differences were dependent on the proportion of PVP present, its molecular weight and method of incorporation. Cumulative urinary excretion data from test capsule preparations showed that bioavailability was enhanced by the presence of PVP. However, the degree of enhancement was less than that expected from constant surface area disc rate studies. Dissolution tests on the capsule formulations, using the U.S.P. basket stirrer assembly, did not correlate with in vivo results. Using the Levy beaker method and a stirring speed of 40 rev min-1, good correlation between amount dissolved in 30 min and amount excreted in urine after 24 h was obtained. The dissolution tests revealed that PVP retards the initial dissolution from capsule dosage forms, probably by retarding deaggregation and dispersion of drug particles.     

Interaction of antacids with antiarrhythmics. V. Effect of aluminium hydroxide and magnesium oxide on the bioavailability of quinidine, procainamide and propranolol in dogs

The influence of aluminium hydroxide and magnesium oxide on the oral bioavailability of quinidine, procainamide and propranolol in the dog was investigated. The administration of aluminium hydroxide with a quinidine sulfate capsule causes a significant decrease of maximal plasma concentration (Cpmax) and a shift in tmax (time to reach Cpmax). The area under the curve is not significantly decreased. Administration of magnesium oxide together with a quinidine sulfate capsule or a sustained-release preparation of quinidine bisulfate causes a significant decrease of both Cpmax and the area under the curve. A shift of tmax was observed for the conventional preparation only. The administration of aluminium hydroxide with procainamide hydrochloride diminishes only Cpmax in a significant way. Administration of magnesium oxide together with procainamide hydrochloride has no influence on the different parameters. Administration of aluminium hydroxide or magnesium oxide with propranolol hydrochloride has a significant negative influence on both the Cpmax and the area under the curve.     

The effect of a combination antacid preparation containing aluminium hydroxide and magnesium hydroxide on rosuvastatin pharmacokinetics

ABSTRACT

Objective: Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of dyslipidaemia, may be co-administered with antacids in clinical practice. This trial assessed the effect of simultaneous and separated administration of an antacid preparation containing aluminium hydroxide 220?mg/5?mL and magnesium hydroxide 195?mg/5?mL (co-magaldrox 195/220) on the pharmacokinetics of rosuvastatin.

Research design and methods: A randomised, open-label, three-way crossover trial was performed. Healthy male volunteers (n = 14) received a single dose of rosuvastatin 40?mg alone, rosuvastatin 40?mg plus 20?mL antacid suspension taken simultaneously, and rosuvastatin 40?mg plus 20?mL antacid suspension taken 2?h after rosuvastatin on three separate occasions with a washout of ≥?7 days between each.

Main outcome measures: The primary parameters were area under the rosuvastatin plasma concentration–time curve from time zero to the last quantifiable concentration (AUC_(0–t)) and maximum observed rosuvastatin plasma concentration (C_max) in the absence and presence of antacid.

Results: When rosuvastatin and antacid were given simultaneously, the antacid reduced the rosuvastatin AUC_(0–t) by 54% (90% confidence interval [CI] for the treatment 0.40–0.53) and C_max by 50% (90% CI 0.41–0.60). When the antacid was given 2?h after rosuvastatin, the antacid reduced the rosuvastatin AUC_(0–t) by 22% (90% CI 0.68–0.90) and the C_max by 16% (90% CI 0.70–1.01). The effect of repeated antacid administration was not studied and it cannot be discounted that this may have resulted in a stronger interaction than that observed here.

Conclusions: Simultaneous dosing with rosuvastatin and antacid resulted in a decrease in rosuvastatin systemic exposure of approximately 50%. This effect was mitigated when antacid was administered 2?h after rosuvastatin.     

口服胃舒平对茶碱药物动力学的影响

以６只家兔单服氨茶碱（Ａ）和同服胃舒平（Ｂ）后茶碱的血药浓度及药物动力学进行研究。结果表明两药同服时，茶碱的血药浓度明显偏低，所得药动学参数经配对ｔ检验，Ｃｍａｘ和ＡＵＣ具有显著性差异（Ｐ＞０．０５），Ｂ与Ａ的ＡＵＣ之比约为８０％，而Ｔ１／２（Ｋａ）、Ｔ１／２（Ｋ）、Ｔｍａｘ无显著性差异（Ｐ＞０．０５）。表明：胃舒平对茶碱的代谢消除无显著影响。但可影响茶碱的吸收，致使茶碱的生物利用度降低约２０％。因此在临床应避免两者同时服用     

食物对环丙沙星生物利用度的影响

本文以9名健康志愿者为试验对象,在空腹和进食条件下分别交叉口服环丙沙星片剂,采用二阶导数分光光度法测定尿药浓度。结果表明:进食对环丙沙星生物利用度无明显影响。空腹和进食条件48h 尿中排药量分别为47%±8%和44%±8.4%(P>0.05)。但进食条件可延缓该药的吸收速率和缓解该药的胃肠道反应。     

Effects of end stage renal disease and aluminium hydroxide on triazolam pharmacokinetics.

Triazolam 0.5 mg was administered to 11 dialysis patients and 11 age, weight and sex matched controls. Peak plasma concentrations (Cmax) were higher in control subjects, but there were no other differences between the groups. When dialysis patients took triazolam with 3600 mg aluminum hydroxide suspension, Cmax and AUC were increased into the range observed in control subjects. It appears that triazolam can be used at normal doses in patients with renal dysfunction, without regard to interaction with aluminum hydroxide gel, or to alterations in elimination.     

Effect of aluminium phosphate on the bioavailability of cimetidine and prednisolone

Summary Ten fasting subjects received 200 mg cimetidine orally either with water or 11 g aluminium phosphate mixture in a randomized, single dose, two-way cross-over study. Blood samples were taken for 12 h and urine was collected for 24 h. Cimetidine in plasma and urine was analysed by HPLC. There were no significant differences between the treatments with respect to peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, and urinary excretion. In 12 healthy subjects the absorption of prednisolone was investigated when given alone and together with 11 g aluminium phosphate. Blood samples were taken over 16 h and prednisolone in plasma was analysed by HPLC. There were no significant differences in the values of area under curve (AUC), C_max and t_max. The results indicate that aluminium phosphate does not reduce the bioavailability of cimetidine and prednisolone.     

Encapsulation of aluminium hydroxide fillers with polymethyl-methacrylate

A process was developed for the microencapsulation of inorganic filler particles with poly-methyl-methacrylate, to increase the interaction between the hydrophilic filler particles and a polymer matrix. The filler utilised was aluminium hydroxide with an average diameter of 1.9 µm and a specific surface area of 5 m2/g. The process comprised a surface modification, in which a monolayer of isopropoxy titanium isostearate was chemically bound to the surface to render it hydrophobic and to ensure a chemical bond between the filler and the organic phase. Then, an encapsulation reaction was carried out by means of an emulsion-like polymerization process at monomer starved conditions. The modified particles were stabilized in water with sodium-dodecyl-sulphate. A redox system consisting of cumene-hydroperoxide in combination with sodium-formaldehyde-sulphoxylate and iron(II) salt was applied for the initiation of the polymerization. Besides surface polymer, free polymer particles were also formed. The parameters which varied were the filler concentration, the concentration of the initiator components and the surfactant concentration. At optimum conditions, ~50% of the added monomer polymerized at the modified filler surface, thus forming encapsulated filler particles. SEM together with TGA analysis indicated that a smooth polymer layer had been formed on the filler surface. At high filler loading, however, coagulation occurred.     

Comparative bioavailability: influence of various diets on the bioavailability of indomethacin

After oral application of 100 mg indomethacin to eight healthy male volunteers, the concentrations in plasma and their time course were determined when the drug was given to fasting individuals or after a high-protein, a high-lipid or a high-carbohydrate meal. The study was designed as a fourfold-crossover experiement with intermissions of at least one week between applications. Indomethacin in plasma was determined by fluorimetry after a double extraction procedure. Indomethacin plasma concentrations and the truncated areas under the curves (AUC) were evaluated. Administration to fasting subjects provides higher plasma levels and a smaller tmax value than after either one of the three diets. Also the absorption rate was higher in fasting individuals. However, the absorbed amount of indomethacin after 24 hr was practically equal in all four groups. Attempts to distinguish between the effects of the various diets revealed significant differences in the time period necessary to reach the peak values. After high-protein and high-lipid diets they were reached in the 90 min sample while after high-carbohydrate 120 min were required. These values are significantly different from fasting controls (45 min) and from each other. There is no great influence of food on the other aspect of bioavailability, amount of unchanged drug reaching the systemic circulation.