Famotidine In Plasma Research Articles

Yoghurt as a deglutition aid for oral medication: effects on famotidine powder dissolution rate and pharmacokinetics

Deglutition aid foods are used to help patients with dysphagia take oral medications. Yoghurt is occasionally used to help swallow medications; however, its influence on pharmacokinetics is poorly understood. Yoghurt made with Lactococcus cremoris subsp. cremoris FC has a characteristic viscous texture that facilitates bolus formation and deglutition due to its metabolite exopolysaccharide. We assessed yoghurt prepared with L. cremoris FC as a food deglutition aid. We performed a dissolution test using famotidine powder mixed with yoghurt and a food thickener. Famotidine dissolution rates without deglutition-assisting foods and with yoghurt or food thickener were 102.3 ± 1.7, 85.7 ± 4.6, and 46.4 ± 1.1% after 15 min, respectively. Next, we orally administered famotidine powder with water, yoghurt, and food thickener to rats and measured plasma famotidine levels. We observed no significant differences between all test groups. The Tmax of famotidine mixed with a food thickener was significantly lower than that with yoghurt. These results suggest that yoghurt with L. cremoris FC did not remarkably affect the dissolution and pharmacokinetic profiles of famotidine powder. Thus, the administration of famotidine with yoghurt might be a suitable alternative to powder administration as a deglutition aid for patients.

Determination of Famotidine in Plasma and Urine by High‐performance Liquid Chromatography

Because therapeutic concentrations of famotidine are low in plasma, a sensitive method is required to determine plasma famotidine concentrations in clinical studies. A sensitive and rapid high-performance liquid chromatographic (HPLC) method was developed for the determination of famotidine in both plasma and urine samples. Ranitidine and cimetidine were used as internal standards for urine and plasma measurements. For plasma, the mobile phase was acetonitrile-water (15 : 85 v/v), 45 mM sodium dodecyl sulphate (SDS) and 20 mM disodium hydrogen phosphate adjusted to pH 3. A mixture of methanol-phosphate buffer (20 : 80 v/v) adjusted to pH 6·3 was used as the mobile phase for the determination of the compound in urine. The separation was performed on an analytical 150 · 3·9 mm i.d. reversed-phase Novapack C18 (4 μm particle size) column using UV detector (267 nm for plasma and 282 nm for urine). The detection limits for famotidine in plasma and urine were 7·5 ng ml−1 and 160 ng ml−1, respectively. The inter- and intra-assay coefficients of variation were found to be less than 10%.

Development of a rapid HPLC method for determination of famotidine in human plasma using a monolithic column

A rapid and sensitive HPLC method using a monolithic column has been developed for quantification of famotidine in plasma. The assay enables the measurement of famotidine for therapeutic drug monitoring with a minimum detectable limit of 5 ng ml −1. The method involves simple, one-step extraction procedure and analytical recovery was complete. The separation was carried out in reversed-phase conditions using a Chromolith Performance (RP-18e, 100 mm × 4.6 mm) column with an isocratic mobile phase consisting of 0.03 M disodium hydrogen phosphate buffer–acetonitrile (93:7, v/v) adjusted to pH 6.5. The wavelength was set at 267 nm. The calibration curve was linear over the concentration range 20–400 ng ml −1. The coefficients of variation for inter-day and intra-day assay were found to be less than 8%.

Sensitive high-performance liquid chromatographic determination of famotidine in plasma: Application to pharmacokinetic study

A sensitive high-performance liquid chromatographic (HPLC) method for the quantitation of famotidine in human plasma is described. Clopamide was used as the internal standard. Plasma samples were extracted with diethyl ether to eliminate endogenous interferences. Plasma samples were then extracted at alkaline pH with ethyl acetate. Famotidine and the internal standard were readily extracted into the organic solvent. After evaporation of ethyl acetate, the residue was analysed by HPLC. The chromatographic separation was accomplished with an isocratic mobile phase consisting of acetonitrile—water (12:88, v/v) containing 20 m M disodium hydrogenphosphate and 50 m M sodium dodecyl sulphate, adjusted to pH 3. The HPLC microbore column was packed with 5 μm ODS Hypersil. Using ultraviolet detection at 267 nm, the detection limit for plasma famotidine was 5 ng/ml. The calibration curve was linear over the concentration range 5–500 ng/ml. The inter- and intra-assay coefficients of variation were found to be less than 10%. Applicability of the method was demonstrated by a bioavailability/pharmacokinetic study in normal volunteers who received 80 mg famotidine orally.

Clinical Pharmacokinetics of Famotidine

Famotidine is a potent histamine H2-receptor antagonist widely used in the treatment and prevention of peptic ulcer disease. After intravenous administration the plasma famotidine concentration-time profile exhibits a biexponential decay, with a distribution half-life of about 0.18 to 0.5h and an elimination half-life of about 2 to 4h. The volume of distribution of the drug at steady-state ranges from 1.0 to 1.3 L/kg; plasma protein binding is low (15 to 22%). Famotidine is 70% eliminated unchanged into urine after intravenous administration. The total body and renal clearances of famotidine correlate significantly with creatinine clearance. Because its renal clearance (15 L/h) far exceeds the glomerular filtration rate, famotidine is considered to be eliminated not only via glomerular filtration but also via renal tubular secretion. Since its clearance is reduced in patients with renal insufficiency and in elderly patients, the maintenance dosage should be reduced in these patient groups. Removal of famotidine by any of the currently employed blood purification procedures (haemodialysis, peritoneal dialysis and haemofiltration) does not occur to a clinically significant degree. Liver cirrhosis does not appear to affect the disposition of famotidine unless severe renal insufficiency coexists. After oral administration, peak plasma concentrations are attained within 2 to 4h; the oral bioavailability ranges from 40 to 50%, due mainly to incomplete absorption. The oral absorption of the drug is dose-independent within a range of 5 to 40 mg. There are 3 formulations available (tablet, capsule and suspension), which appear to be bioequivalent. Coadministration of potent antacids reduces the oral absorption of famotidine by 20 to 30%. On a weight-to-weight basis, the antisecretory effect of famotidine is about 20 and 7.5 times more potent than those of cimetidine and ranitidine, respectively. Plasma famotidine concentrations correlate with its antisecretory effect: values of about 13 and 20 micrograms/L produce a 50% reduction in the gastrin-stimulated gastric acid secretion and a fasting intragastric pH of greater than 4, respectively. Available data suggest that famotidine interacts neither with the hepatic oxidative drug metabolism nor with the tubular secretion of other commonly used therapeutic agents. However, further studies are required to evaluate a full spectrum of its drug interaction potential.

Pharmacokinetics of famotidine in normal subjects and in patients with chronic liver disease

The pharmacokinetics of famotidine were studied in seven healthy control subjects and in 14 patients with cirrhosis, following single oral and intravenous 20-mg dose administration, and after seven daily doses of 40 mg. Following intravenous (i.v.) administration, the mean (range) total plasma clearance values were not significantly different in the patients with compensated cirrhosis (n = 7), 337 (241-576) ml/min or in the patients with decompensated cirrhosis (n = 7), 270 (120-408) ml/min compared with the control group, 370 (154-612) ml/min. The mean half-life in the compensated cirrhotics, 2.86 (1.87-4.98) h, was similar to that in the control group 2.91 (1.86-6.03) h, but it was insignificantly prolonged in the decompensated cirrhotics 3.35 (2.00-5.77) h. The mean, maximum, plasma famotidine concentrations after single oral doses were comparable between the groups but there was considerable inter-subject variability, with individual values ranging from 17 to 139 ng/ml. Peak plasma concentrations were reached within 2-3 h, although more variability was observed among patients with decompensated cirrhosis. The mean systemic availability of the drug, estimated from urinary recovery, was 0.39 (0.15-0.64) in the healthy controls, 0.35 (0.14-0.51) in the patients with compensated cirrhosis and 0.38 (0.13-0.77) in the patients with decompensated cirrhosis. No significant increases were observed in plasma trough famotidine concentrations following multiple oral dosing in any of the subjects, and the kinetic variables after the seventh dose were not significantly different from those following the single oral dose. No significant changes were observed in psychometric performance in control subjects or in patients between the pre-study day and day seven of the multiple oral dose phase.

Famotidine

The pharmacokinetic and pharmacodynamic properties of the H2-receptor antagonist famotidine have been well described in adult subjects. However, similar data for children are not available. Therefore, this study looked at the disposition of the drug (given to prevent aspiration following cardiac surgery) in 10 paediatric patients with normal kidney function (age range 2 to 7 years, bodyweight 14 to 25 kg) after a single intravenous dose of famotidine 0.3 mg/kg. Plasma concentrations of the drug and gastric pH values were both monitored for 20 hours by high performance liquid chromatography and aspiration of gastric juice, respectively. Plasma famotidine concentrations declined with an elimination half-life of 3.3 +/- 1.8 h (mean +/- SD) and the drug was effective in elevating the gastric pH above 3.5 for about 9 hours in 6 patients. The variable volume of distribution and total plasma clearance of famotidine averaged 1.4 +/- 1.0 L/kg and 0.3 +/- 0.17 L/h/kg, respectively. In 4 patients unchanged famotidine could also be measured in a 12-hour urine fraction. The amount excreted (21 to 79%) correlated with clearance (r = 0.97). All these data are comparable to those obtained in healthy adults, indicating that paediatric patients receiving intensive medical treatment after cardiac surgery can handle famotidine in a way very similar to healthy adult subjects. A dosage of 0.3 mg/kg every 8 hours appears to be advisable.

Impaired Bioavailability of Famotidine Given Concurrently with a Potent Antacid

The effect of a high potency antacid on the oral bioavailability of a single dose of famotidine (40 mg) was evaluated in normal volunteers according to a randomized cross-over design. Ingestion of the antacid concurrently with famotidine resulted in a significant reduction of peak plasma famotidine concentration (from 156 +/- 22 to 104 +/- 7, P less than 0.05) and area under the famotidine plasma concentration curve (from 956 +/- 125 to 607 +/- 56, P less than 0.02). No significant interaction was observed when the antacid was ingested 2 hours after famotidine administration.

Plasma famotidine concentration versus intragastric pH in patients with upper gastrointestinal bleeding and in healthy subjects

To study the concentration-response relationship of famotidine, we serially monitored intragastric pH and measured plasma drug concentrations simultaneously after an intravenous injection of this H2-receptor antagonist (0.1 mg/kg) in eight patients with upper gastrointestinal bleeding and in six healthy subjects. By applying the sigmoidal Emax model the mean (+/- SD) plasma famotidine concentrations associated with an intragastric pH of 4.0 in patients and healthy subjects were estimated to be 17.7 +/- 10.7 and 24.8 +/- 10.3 ng/ml, respectively (not significantly different). No significant differences were observed in the mean pharmacokinetic parameters between the two study groups. Multiple regression analysis revealed that not only a pharmacokinetic factor (i.e., elimination t1/2) but also a pharmacodynamic (or sensitivity) factor (i.e., a drug concentration associated with an intragastric pH of 4.0) contributed significantly (p less than 0.01) to the overall variability in the duration of antisecretory effect in our study subjects, with standardized partial regression coefficients of 0.54 and -0.63, respectively. Based on these data, we predict that around-the-clock control of a fasting intragastric pH above 4.0 can be attained by a continuous infusion of famotidine at rates ranging from 6 to 25 mg/day (mean +/- SD, 11 +/- 7 mg/day) in a 70 kg patient whose pharmacokinetic and pharmacodynamic characteristics are similar to those of our patients.

Determination of famotidine in plasma, urine and gastric juice by high-performance liquid chromatography using disposable solid-phase extraction columns

Determination of famotidine in plasma, urine and gastric juice by high-performance liquid chromatography using disposable solid-phase extraction columns

Is the bioavailability of famotidine reduced by an antacid?

Famotidine is a potent histamine H2-receptor now undergoing clinical trial in Italy, Germany, the UK, France, and the USA, and has just come on the market in Japan. To study the effect of concurrent antacid administration on the oral absorption of famotidine, 10 subjects (8 patients with peptic ulcer, 2 normal adults) received 20 mg (5 subjects) or 40 mg (5 subjects) of famotidine with and without Maalox (aluminum hydroxide and magnesium hydroxide). Slight declines in the maximum plasma concentration and the areas under the plasma concentration time curve of famotidine were observed when an antacid was given simultaneously, indicating that concurrent antacid decreases the bioavailability of this new antisecretory compound. Although the plasma famotidine level was lowered by concurrent administration of antacid, it remained higher than the plasma concentration for 50% inhibition of stimulated acid secretion (IC50) for up to 12 hours.