Comparative bioavailability of two oral formulations of ranitidine.

The current requirement of the Mexican Authorities to demonstrate the interchangeability of ranitidine formulations is to establish that the dissolution profile of the drug shows similarity. In order to establish if this requirement is adequate, the bioavailability of two formulations that did not meet this similarity were compared. Twenty-five female volunteers received 150 mg ranitidine (Azantac or Midaven) under fasting conditions in two separate sessions using a cross-over design. Plasma samples were obtained at selected times for a period of 12 h and stored frozen at -80 degrees C until analysed. Ranitidine plasma levels were determined and pharmacokinetic parameters were obtained. Values (mean+/-SEM) were: Cmax 528.85+/-25.34 and 563.03+/-33.25 ng/ml, tmax 2.76+/-0.19 and 2.79+/-0.18 h, and AUC12 h 2694.94+/-99.50 and 2648.51+/-133.38 ng.h/ml, for Azantac or Midaven, respectively. No statistically significant difference was obtained in the parameters evaluated. Moreover, 90% confidence limits were 96.6%-116.2% and 90.7%-105.1% for Cmax and AUC12 h ratios, respectively, indicating that the formulations tested are bioequivalent, despite the dissimilarity in the dissolution profile of the formulations. These results suggest that the comparative dissolution profile is not an adequate test to demonstrate the interchangeability of ranitidine formulations.

Effect of age on the pharmacokinetics of ranitidine in healthy Mexican volunteers.

UNLABELLED: Numerous reports in the literature have demonstrated changes in drug pharmacokinetics that result with age. Ranitidine is a drug commonly used in Mexico. However no reports on the pharmacokinetics of ranitidine in the Mexican population are available in the literature. The objective of this clinical trial was to evaluate the effect of age on the pharmacokinetics of ranitidine in healthy Mexican volunteers. METHODS: Twenty-one healthy Mexican volunteers were included, who were divided into three groups G1 (18-30 y), G2 (31-50 y) and G3 (51-60 y). The volunteers were given a single oral dose of 300 mg of ranitidine and blood samples were obtained, and some pharmacokinetic parameters were correlated with age. RESULTS: Statistically significant differences were noted in the distribution volume (4.00 +/- 1.11 L/kg in G1, vs 2.15 +/- 1.12 L/kg in G3) of the drug. Clearance was faster among the G1 (1.11 +/- 0.12 mL/hr) group compared to the G3 group (0.58 +/- 0.19 mL/hr). Differences for AUC, t1/2 and Cmax are more evident between G1 and G3. DISCUSSION: The results of our study indicated that in patients over 50 years of age who are treated with ranitidine, the dosage of this agent should be appropriately adjusted in order to avoid adverse effects that may develop with prolonged use of the drug. However it is very important to consider that our result only reflect observations made from a single dose study, thus it is necessary to carry out study under chronic dosage treatment.

Comparison of two compartmental models for describing ranitidine's plasmatic profiles.

The plasmatic profiles of 12 healthy volunteers after oral administration of ranitidine (150 mg) were studied considering two compartmental models. We observed the presence of two peaks. The proposed mechanism responsible for the existence of secondary peaks includes enterohepatic recirculation and the existence of multiple sites of absorption along the gastrointestinal tract. For characterizing the pharmacokinetic aspect of the drug, both phenomena were described using two compartmental models. We calculated the pharmacokinetic parameters and statistical tests after fitting the data of each volunteer under both models proposed. Statistically significant differences were not found in the statistical test values but existed in the area under the curve (AUC) comparing between models. To decide which of the two proposed models gave the best approximation of the physiological phenomenon undergone, we studied the pharmacokinetic of the drug in the rat, an animal without gallbladder. After oral administration of ranitidine, the plasmatic profile of the animals showed at least two peaks. Less than 0.2% of an oral dose was recovered in bile as ranitidine. Therefore, and considering the rat has no post-absorptive depot from where the drug can be released discontinuously, enterohepatic recycling does not seem to contribute significantly to the occurrence of secondary peaks in the concentration-time profiles of rats. Considering the results, we proposed that the best model able to explain the plasmatic profiles found in man and rats after oral administration of ranitidine is the one that presents multiple sites of absorption along the gastrointestinal tract. It is important to define the correct model in the calculation of the AUC and so in the value of the absolute bioavailability.

Farmacología clínica de los antihistamínicos en medicina veterinaria / Clinical pharmacology of antihistaminic agents in veterinary medicine

A pesar de que los antihistamínicos se utilizan rutinariamente en mayor o menor medida en medicina veterinaria, poco se ha escrito sobre ellos y, por ende, existen pocos estudios formales que permiten juzgar su eficacia clínica. Aunque su advenimiento es posterior, existen más informes sobre los antihistamínicos de receptores H2 que de los H1 y son pocos los datos que ofrece la literatura acerca del uso de los inhibidores de la liberación de histamina. En parte, esta escases de informes especializados en la literatura científica, se debe a que es difícil cuantificar el alivio o bienestar que inducen los antihistamínicos. Sin embargo, es claro que por su antagonismo con histamina, pueden ayudar a la resolución de variadas enfermedades en las especies domésticas. En este sentido se presenta una revisión de la literatura, encaminada a ofrecer al lector los datos clínicos disponibles, así como las enfermedades en las que estos agentes podrían ser de utilidad. En virtud de que existen pocos datos de la farmacocinética de estos compuestos en medicina veterinaria, en particular de los antiH1, se presentan los correspondientes en humanos, pero sólo como referencia ya que es sabido que la extrapolación conduce a graves errores. Son necesarios estudios en cada especie doméstica. Asimismo se tienen disponibles las dosis de todos los antihistamínicos en las diversas especies domésticas ni para todas la indicaciones; por ello se hace referencia a las dosis empíricas usadas en veterinaria y lo establecido en humanos. Cuando es pertinente, se comenta el uso de los antihistamínicos en humanos, a fin de estimular a los investigadores a extrapolar de datos en ensayos clínicos

Effects of age and chronic renal failure on the urinary excretion kinetics of famotidine in man.

The plasma and urine concentrations of famotidine, a new, potent H2-receptor antagonist, have been measured in 16 healthy young adults, 8 healthy elderly people and 18 patients with varying degrees of renal dysfunction after intravenous administration. Both the plasma elimination and renal excretion of famotidine were decreased in the elderly volunteers and renal patients. The renal clearance of famotidine averaged 4.43 ml/min/kg (310 ml/min) in normal young volunteers, which exceeded the mean creatinine clearance 1.55 ml/min/kg (109 ml/min), suggesting net secretion is a significant mechanism for elimination of famotidine. The ratio of famotidine renal clearance to creatinine clearance decreased as creatinine clearance decreased; these results suggest that the deterioration in the secretion process was much faster than that in glomerular filtration and are incompatible with the "intact nephron hypothesis". Nevertheless, both total body clearance and renal clearance were significantly correlated with creatinine clearance. The apparent half-life was also significantly correlated with creatinine clearance. Since famotidine is essentially free of dose-related adverse effects, dose adjustment in patients with mild renal insufficiency and in elderly people is not required; however, either a prolonged dosing interval or a decrease in daily dose during long-term therapy may be adapted for the patients with severe renal insufficiency to avoid accumulation and the potential undesirable effects.