Comparative bioavailability of three ibuprofen formulations in healthy human volunteers.

OBJECTIVE: To assess the bioequivalence of three ibuprofen formulations (Test formulation: ibuprofen (400 mg capsule) manufactured by Cardinal Health Brasil 402 Ltda. (Sorocaba, Brazil) and licensed to Boehringer Ingelheim do Brasil Quim. e Farm. Ltda. (SA poundo Paulo, Brazil); Reference formulation (1): ibuprofen (AdvilA(R); 2 A 200 mg coated tablet) from Wyeth-Whitehall Ltda. (Itapevi, Brazil); Reference formulation (2): ibuprofen (AliviumA; 8 ml A 50 mg/ml solution) from Schering Plough S.A. (Rio de Janeiro, Brazil)) in 24 healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, three-period crossover design with at least 5-day washout interval. Plasma samples were obtained over a 24-h period. Plasma ibuprofen concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with negative ion electrospray ionization using multiple reaction monitoring (MRM). The following pharmacokinetic parameters were obtained from the ibuprofen plasma concentration vs. time curves: AUC(last), AUC(trunctmax), AUC(inf) and C(max). RESULTS: The limit of quantification for ibuprofen was 0.1 microg A ml(1). The geometric mean with corresponding 90% confidence interval (CI) for Test/Reference (1) percent ratios were 114.24% (90% CI = 105.67, 123.50%) for C(max), 98.97% (90% CI = 94.69, 103.44%) for AUC(last) and 99.40% (90% CI = 95.21, 103.78%) for AUC(inf). The geometric mean and respective 90% confidence interval (CI) for Test/Reference (2) percent ratios were 108.38% (90% CI = 100.19, 117.25%) for C(max), 100.79% (90% CI = 96.39, 105.40%) for AUC(last) and 101.26% (90% CI = 96.94, 105.77%) for AUC(inf); t(max) for the 400 mg Test capsule was shorter than that for the 2 A 200 mg Reference (1) tablets (p < 0.002). CONCLUSION: Since the 90% CI for AUC(last), AUC(inf) and Cmax ratios were within the 80 - 125% interval proposed by the US FDA, it was concluded that ibuprofen formulation manufactured by Cardinal Health Brasil 402 Ltda. and licensed to Boehringer Ingelheim do Brasil Quim. e Farm. Ltda. is bioequivalent to the AdvilA and AliviumA formulations with regard to both the rate and the extent of absorption.

A bioequivalence study of gliclazide based on quantification by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry.

OBJECTIVE: The aim of this study was to evaluate, in human volunteers, the performance of one gliclazide tablet formulation (gliclazide 80 mg tablet from EMS Indústria Farmacêutica Ltda.) against two reference gliclazide tablet formulations (Diamicron 80 mg tablet from Servier do Brazil Ltda. and Diamicron 80 mg tablet from Servier (Ireland) Industries Limited). METHODS: The study had an open, randomized, three-period crossover design with a one-week washout interval between doses. The samples were obtained over a 48-h interval after each oral administration of gliclazide. The samples were extracted from plasma using diethylether : hexane (80 : 20, v/v) and the extracts were analyzed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/ MS). Chromatography was performed isocratically using a Jones Chromatography Genesis C8 120A 4u. The method had a chromatographic run-time of 2.5 min and a calibration curve of the range of 0.02- 10 microg x ml(-1) (r(2) > 0.9993). The limit of quantification was 0.02 microg x ml(-1). RESULTS: The geometric mean and 90% confidence intervals (CI) for the Gliclazide/Diamicron (Ireland) ratio were 588.68% (90% CI= 491.16, 705.58%) for AUClast, 423.50% (90% CI = 338.25, 530.23%) for AUCinf, and 1395.77% (90% CI= 1116.62, 1744.72%) for Cmax. The geometric mean and 90% confidence intervals (CI) for the Gliclazide/Diamicron (Brazil) ratio were 249.16% (90% CI = 207.96, 298.54%) for AUCiast, 249.16% (90% CI = 207.96 - 298.54%) for AUCinf, and 188.04% (90% CI - 151.72, 233.05%) for Cmax. CONCLUSION: Since the 90% CI for Cmax, AUClast and AUC(0-infinity) ratios were all outside the 125% interval proposed by the US Food and Drug Administration, we concluded that the gliclazide test formulation were not bioequivalent to either reference formulation. Interestingly, the pharmacokinetic parameters such as Cmax, AUClast of both reference formulations are compatible with neither the literature nor the profile of an immediate release formulation. In addition, both reference formulations were not bioequivalent in themselves, indicating significant differences in reference product formulation.

Transfer of clarithromycin to gastric juice is enhanced by omeprazole in Helicobacter pylori-infected individuals.

BACKGROUND: The effects of proton-pump inhibitors and Helicobacter pylori infection on the distribution of drugs employed for the eradication of H. pylori are poorly understood. The aim of this study was to investigate the effects of a 7-day oral administration of 20 mg omeprazole on the distribution of clarithromycin in the gastric juice of individuals with H. pylori infection. METHODS: Eighteen H. pylori-infected dyspeptic male volunteers without endoscopic lesions were enrolled in a study with an open, randomized, two-period crossover design and a 21-day washout period between phases. Plasma and gastric juice concentrations of clarithromycin in subjects with and without omeprazole pretreatment were measured by means of liquid chromatography coupled to tandem mass spectrometry. RESULTS: The maximum concentration of clarithromycin (Cmax) and the area under the time-concentration curve from 0 to 2 h (AUC0-2h) were significantly higher in gastric juice than in plasma. Omeprazole treatment further augmented clarithromycin Cmax and AUC0-2h in gastric juice approximately 2-fold (P < 0.05). CONCLUSIONS: Short-term treatment with omeprazole in H. pylori-positive volunteers increases the amount of clarithromycin transferred to the gastric juice, confirming a synergism between these drugs. Our results suggest the presence of an active transport mechanism for clarithromycin from plasma to the gastric lumen, which is influenced by omeprazole.

Transfer of metronidazole to gastric juice: impact of Helicobacter pylori infection and omeprazole.

BACKGROUND: The effects of Helicobacter pylori infection associated with inhibition of gastric acid secretion on the distribution of medications used for H. pylori eradication are poorly understood. The aim of this study was to investigate the effects of a 7-day administration of 20 mg omeprazole on the transfer of metronidazole from plasma to the gastric juice of individuals with and without H. pylori infection. METHODS: Fourteen H. pylori-positive and 14 H. pylori-negative male volunteers were enrolled in a study with an open, randomized, two-period crossover design with a 21-day washout period between phases. Plasma, salivary, and gastric juice concentrations of metronidazole in subjects with and without omeprazole treatment were measured with reversed-phase high-performance liquid chromatography/liquid chromatography. RESULTS: Metronidazole peak concentration (Cmax) was similar in plasma and saliva and was approximately threefold higher in gastric juice in all groups. Omeprazole treatment increased gastric pH and did not affect metronidazole Cmax or the time required for this to be reached (tmax) in plasma, saliva, or gastric juice. However, omeprazole significantly reduced metronidazole transfer from plasma to gastric juice in H. pylori-positive but not H. pylori-negative subjects, as shown by statistical analysis of AUC(0-2 h). CONCLUSION: Short-term treatment with omeprazole in H. pylori- positive volunteers reduces the amount of metronidazole transferred from plasma to gastric juice. This seems to occur in a pH-independent form.

Acid suppression by omeprazole does not affect orally administered metronidazole bioavailability and metabolism in healthy male volunteers.

BACKGROUND: The addition of omeprazole to classical triple therapy for eradication of H. pylori may enhance compliance through reducing ulcer symptoms and side-effects. The aim of this study was to investigate the effects of a 5-day administration of omeprazole on metronidazole pharmacokinetics. METHODS: Fourteen healthy male volunteers were selected. The study had an open, randomized, two-period crossover design with a 21-day washout period between the phases. Plasma concentrations of metronidazole and its hydroxy-metabolite were measured by reversed-phase HPLC with ultraviolet detection. RESULTS: Administration of omeprazole did not affect the pharmacokinetic parameters of orally administered metronidazole. CONCLUSION: Our results indicate that short-term treatment with omeprazole in healthy volunteers does not alter the extent or the rate of metronidazole absorption, and does not affect metronidazole clearance.

Short-term sucralfate administration alters potassium diclofenac absorption in healthy male volunteers.

AIMS: Since patients who regularly take NSAIDS may use sucralfate because of its cytoprotective properties, we examined the influence of this compound on the pharmacokinetics of diclofenac. METHODS: Potassium diclofenac (105 mg) was administered orally to eighteen healthy male volunteers with or without a 5-day pre-treatment with sucralfate (2000 mg twice daily). Blood samples were collected at intervals post-dose and serum concentrations of diclofenac were determined by reverse-phase h.p.l.c. RESULTS: Pre-treatment with sucralfate significantly decreased both the AUC(0,8 h) [2265 ng h ml-1 (geometric mean) (range 1815-2827) vs 1821 ng h ml-1 (1295-2562)] and the Cmax [1135 ng ml-1 (geometric mean) (range 898-1436) 701 ng ml-1 (501-981)] with no significant delay in absorption [tmax 1.0 h (median) (range 0.5-2.0) vs 1.0 h (0.5-4.0)]. CONCLUSIONS: The short-term treatment of healthy male volunteers with sucralfate decreases potassium diclofenac bioavailability. These findings suggest that either an appropriate increase in the diclofenac intake or the use of another gastric mucosa protector must be adopted.