Functional Investigation of Solute Carrier Family 35, Member F2, in Three Cellular Models of the Primate Blood-Brain Barrier.

Understanding the mechanisms of drug transport across the blood-brain barrier (BBB) is an important issue for regulating the pharmacokinetics of drugs in the central nervous system. In this study, we focused on solute carrier family 35, member F2 (SLC35F2), whose mRNA is highly expressed in the BBB. SLC35F2 protein was enriched in isolated mouse and monkey brain capillaries relative to brain homogenates and was localized exclusively on the apical membrane of MDCKII cells and brain microvascular endothelial cells (BMECs) differentiated from human induced pluripotent stem cells (hiPS-BMECs). SLC35F2 activity was assessed using its substrate, YM155, and pharmacological experiments revealed SLC35F2 inhibitors, such as famotidine (half-maximal inhibitory concentration, 160 µM). Uptake of YM155 was decreased by famotidine or SLC35F2 knockdown in immortalized human BMECs (human cerebral microvascular endothelial cell/D3 cells). Furthermore, famotidine significantly inhibited the apical (A)-to-basal (B) transport of YM155 in primary cultured monkey BMECs and hiPS-BMECs. Crucially, SLC35F2 knockout diminished the A-to-B transport and intracellular accumulation of YM155 in hiPS-BMECs. By contrast, in studies using an in situ brain perfusion technique, neither deletion of Slc35f2 nor famotidine reduced brain uptake of YM155, even though YM155 is a substrate of mouse SLC35F2. YM155 uptake was decreased significantly by losartan and naringin, inhibitors for the organic anion transporting polypeptide (OATP) 1A4. These findings suggest SLC35F2 is a functional transporter in various cellular models of the primate BBB that delivers its substrates to the brain and that its relative importance in the BBB is modified by differences in the expression of OATPs between primates and rodents. SIGNIFICANCE STATEMENT: This study demonstrated that SLC35F2 is a functional drug influx transporter in three different cellular models of the primate blood-brain barrier (i.e., human cerebral microvascular endothelial cell/D3 cells, primary cultured monkey BMECs, and human induced pluripotent stem-BMECs) but has limited roles in mouse brain. SLC35F2 facilitates apical-to-basal transport across the tight cell monolayer. These findings will contribute to the development of improved strategies for targeting drugs to the central nervous system.

Physiologically-Based Pharmacokinetic Modelling of Creatinine-Drug Interactions in the Chronic Kidney Disease Population.

Elevated serum creatinine (SCr ) caused by the inhibition of renal transporter(s) may be misinterpreted as kidney injury. The interpretation is more complicated in patients with chronic kidney disease (CKD) due to altered disposition of creatinine and renal transporter inhibitors. A clinical study was conducted in 17 patients with CKD (estimated glomerular filtration rate 15-59 mL/min/1.73 m2 ); changes in SCr were monitored during trimethoprim treatment (100-200 mg/day), administered to prevent recurrent urinary infection, relative to the baseline level. Additional SCr -interaction data with trimethoprim, cimetidine, and famotidine in patients with CKD were collated from the literature. Our published physiologically-based creatinine model was extended to predict the effect of the CKD on SCr and creatinine-drug interaction. The creatinine-CKD model incorporated age/sex-related differences in creatinine synthesis, CKD-related glomerular filtration deterioration; change in transporter activity either proportional or disproportional to glomerular filtration rate (GFR) decline were explored. Optimized models successfully recovered baseline SCr from 64 patients with CKD (geometric mean fold-error of 1.1). Combined with pharmacokinetic models of inhibitors, the creatinine model was used to simulate transporter-mediated creatinine-drug interactions. Use of inhibitor unbound plasma concentrations resulted in 66% of simulated SCr interaction data within the prediction limits, with cimetidine interaction significantly underestimated. Assuming that transporter activity deteriorates disproportional to GFR decline resulted in higher predicted sensitivity to transporter inhibition in patients with CKD relative to healthy patients, consistent with sparse clinical data. For the first time, this novel modelling approach enables quantitative prediction of SCr in CKD and delineation of the effect of disease and renal transporter inhibition in this patient population.

Slow-release of famotidine from tablets consisting of chitosan/sulfobutyl ether ß-cyclodextrin composites.

An intermolecular complex formed from a 1:1 weight ratio of chitosan (CS, molecular weight 30 kDa) and sulfobutyl ether ß-cyclodextrin (SBE-ß-CyD, degree of substitution 7) was less soluble than either of the original components. The release of famotidine from tablets composed of a simple mixture of CS and SBE-ß-CyD is slower in media at pH 1.2 than at 6.8. Macroscopic observation of tablets and a kinetic analysis of release profiles suggested that, at pH 1.2, the drug was slowly released from the less-soluble CS/SBE-ß-CyD complex formed on the surface of the tablet immediately after exposure to water, accompanied by the dissolution of the interpolymer complex and, ultimately, the erosion and disintegration of the tablet. In the case of the medium at pH 6.8, the formation of a gel by CS was the cause of the slow release, especially for CS/SBE-ß-CyD tablets which were significantly gelated and both the diameter and thickness of the tablet had expanded. The in vitro slow releasing characteristic of the CS/SBE-ß-CyD tablet was reflected in the in vivo absorption of the drug after oral administration to rats. These results suggest that a simple mixing of CS and SBE-ß-CyD is potentially useful for the controlled release of a drug.

Oral sulfasalazine as a clinical BCRP probe substrate: pharmacokinetic effects of genetic variation (C421A) and pantoprazole coadministration.

This study evaluated the utility of oral sulfasalazine as a probe substrate for Breast Cancer Resistance Protein (BCRP; ABCG2) activity by assessing the impact of genetic variation or coadministration of an inhibitor (pantoprazole) on plasma and urine pharmacokinetics of sulfasalazine and metabolites. Thirty-six healthy male subjects prescreened for ABCG2 421CC (reference activity), CA, and AA (lower activity) genotypes (N = 12 each) received a single 500 mg oral dose of enteric coated sulfasalazine alone, with 40 mg pantoprazole, or with 40 mg famotidine (gastrointestinal pH control) in a 3-period, single fixed sequence, crossover design. No significant difference in sulfasalazine or metabolite pharmacokinetics in 421AA or CA compared to 421CC subjects was found; however, high inter-subject variability was observed. Geometric mean (95% CI) sulfasalazine plasma AUC((0-infinity)) values were 32.1 (13.2, 78.1), 16.8 (7.15, 39.6) and 62.7 (33.4, 118) microg h/mL, and C(max) were 4.01 (1.62, 9.92), 1.70 (0.66, 4.40), and 6.86 (3.61, 13.0) microg/mL for CC, CA, and AA subjects, respectively. Pantoprazole and famotidine did not affect sulfasalazine pharmacokinetics in any genotypic cohort. These results suggest that the pharmacokinetics of oral, enteric-coated 500 mg sulfasalazine are not sufficiently sensitive to ABCG2 genetic variation or inhibitors to be useful as a clinical probe substrate of BCRP activity.

Release mechanisms behind polysaccharides-based famotidine controlled release matrix tablets.

Polysaccharides, which have been explored to possess gelling properties and a wide margin of safety, were used to formulate single-unit floating matrix tablets by a direct compression technique. This work has the aim to allow continuous slow release of famotidine above its site of absorption. The floating approach was achieved by the use of the low density polypropylene foam powder. Polysaccharides (kappa-carrageenan, gellan gum, xyloglucan, and pectin) and blends of polysaccharides (kappa-carrageenan and gellan gum) and cellulose ethers (hydroxypropylmethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose) were tried to modulate the release characteristics. The prepared floating tablets were evaluated for their floating behavior, matrix integrity, swelling studies, in vitro drug release studies, and kinetic analysis of the release data. The differential scanning calorimetry and Fourier transform infrared spectroscopy studies revealed that changing the polymer matrix system by formulation of polymers blends resulted in formation of molecular interactions which may have implications on drug release characteristics. This was obvious from the retardation in drug release and change in its mechanistics.

Efficacy of famotidine for the prevention of exercise-induced gastritis in racing Alaskan sled dogs.

BACKGROUND: Omeprazole reduces the severity of exercise-induced gastritis but not the prevalence of gastric lesions in sled dogs. The frequent feeding of sled dogs during competition likely results in decreased absorption of omeprazole and, thereby, decreased efficacy. HYPOTHESIS: Famotidine, a histamine-2 blocker with good bioavailability in the presence of food, would reduce the incidence and severity of exercise-induced gastric disease in sled dogs. ANIMALS: Sixteen fit Alaskan sled dogs (4 female, 12 male, all intact, age 2-6 years). METHODS: Dogs were randomly assigned to treatment (22 mg famotidine PO q24h) or control groups (n = 8 per group). Famotidine was administered with a meal to the treatment group once daily for 7 days before a challenge and once during exercise. Control dogs were fed an identical diet as the principal group. The 16 dog team completed a 100-mile exercise challenge in 18 hours. A gastroscopy was performed 24 hours after the challenge. The appearance of the mucosa was scored by an individual by using a scoring system. RESULTS: Treatment with famotidine significantly reduced the severity score compared with control (P = .0004). No adverse effects of treatment were reported. CONCLUSIONS AND CLINICAL RELEVANCE: Famotidine is effective in reducing the severity of exercise-induced gastric disease in racing Alaskan sled dogs, with minimal to no adverse effects, and may be recommended for prophylactic use in short distance races.

Formulation and evaluation of famotidine floating tablets.

The purpose of this investigation was to prepare a gastroretentive drug delivery system of famotidine. Floating tablets of famotidine were prepared employing two different grades of methocel K100 and methocel K15M by effervescent technique; these grades of methocel were evaluated for their gel forming properties. Sodium bicarbonate was incorporated as a gas-generating agent. The floating tablets were evaluated for uniformity of weight, hardness, friability, drug content, in vitro buoyancy and dissolution studies. The effect of citric acid on drug release profile and floating properties was investigated. The prepared tablets exhibited satisfactory physico-chemical characteristics. All the prepared batches showed good in vitro buoyancy. The tablet swelled radially and axially during in vitro buoyancy studies. It was observed that the tablet remained buoyant for 6-10 hours. Decrease in the citric acid level increased the floating lag time but tablets floated for longer duration. A combination of sodium bicarbonate (130mg) and citric acid (10mg) was found to achieve optimum in vitro buoyancy. The tablets with methocel K100 were found to float for longer duration as compared with formulations containing methocel K15M. The drug release from the tablets was sufficiently sustained and non-Fickian transport of the drug from tablets was confirmed.

Variability in renal clearance of substrates for renal transporters in chinese subjects.

The authors evaluated the inter- and intraindividual variability in the renal clearance of substrates of organic anion transporters (OAT) or organic cation transporters (OCT) using repeated drug application procedures. Two OAT substrates (ampicillin and cephalexin) and 2 OCT substrates (famotidine and metformin) were selected. Each drug was administered orally twice to healthy subjects, with sample sizes ranging from 12 to 28 (using bioequivalent formulations of each drug). The inter-(delta(inter)) and intrasubject (delta(intra)) variances in renal clearance were estimated based on analysis of variance, and the genetic contribution (r(GC)) was calculated as (delta(inter - intra))/delta(inter). The renal clearances of ampicillin, cephalexin, famotidine, and metformin averaged 5.21 (range, 2.87-11.20), 3.01 (range, 1.50-3.82), 4.96 (range, 2.84-8.17), and 9.44 (range, 5.66-15.43) mL/min/kg, with mean intraindividual coefficients of variation of 17.7%, 7.3%, 13.5%, and 9.0% and r(GC) values of 0.75, 0.89, 0.81, and 0.93, respectively. These high r(GC) values suggest a potential significant genetic contribution by the renal OATs and OCTs in Chinese subjects. Further studies in a larger population are needed to confirm the importance of these results as well as to identify specific genetic variants in these transporters responsible for such variability.

Caco-2 cell culture as a model for famotidine absorption.

The aim of the study was to determine penetration properties of Famotidine fro the formulations through colon adenocarcinoma (Caco)-2 cell monolayers and to compare in vitro with in vivo test results. It also aimed to determine the effect of particle size on the penetration properties of Famotidine when microsphere formulations were used. Famotidine was chosen as a model drug and Caco-2 cell culture model was used. Biodegradable Famotidine microspheres of poly(lactide-co-glycolide)(PLGA) polymer (50:50) were prepared by using multiple emulsion technique. Microspheres were coded according to their particle size and polymer[LHIV:60 microm Famotidine-PLGA(high viscosity), SHIV:6 microm Famotidine PLGA(high viscosity), LLIV:60 microm Famotidine-PLGA (low viscosity), SLIV:6 microm Famotidine-PLGA (low viscosity)]. Famotidine solution(5 mg/ml) and microsphere formulations were administered orally to mice and blood drug levels were determined and compared with the Caco-2 cell experiments. Permeability values of Famotidine through Caco-2 cells from various formulations were determined (log k(solution) = 7,274 +/- 0,010,log kSHIV = -3,884 +/- 0,033,log kLHIV = -2,300 +/- 0,009,log kSLIV = -4,076 +/- 0,208,log kLLIV = 3,525 +/- 0,045). Our results showed that H2 receptor antagonists alter the barrier properties of the Caco-2 cell monolayer by causing an increment in the tightness of the tight junctions. Therefore, amount of the H2 receptor antagonist-like drug at the site of action was found to be important as well as polymer type and particle size of microspheres for drug permeation. Permeation of the drug was lower when higher amounts of Famotidine were present at the diffusion site. A controlled release dosage form of H2 receptor antagonist-like drugs may be beneficial for long-term treatments.

Pharmacokinetics of famotidine in patients with cystic fibrosis.

Famotidine pharmacokinetics were studied in 13 patients with severe cystic fibrosis (CF) ranging from 10 to 47 years of age and 25 to 72 kg in weight. Patients were randomized to first receive famotidine either 20 mg intravenously or 40 mg orally. Twelve patients were crossed over to the alternate treatment. Repeated blood samples were obtained over 12 hours after intravenous and oral administration and urine was collected over 24 hours for quantitation of famotidine by means of high-performance liquid chromatography (HPLC). A compartment model-dependent approach was used to characterize the disposition of famotidine. From the intravenous data, the mean +/- standard deviation elimination half-life (t1/2) was 2.11 +/- 0.75 hours, the total clearance (Cl) was 0.79 +/- 0.41 L/kg/hr, the renal clearance was 0.57 +/- 0.26 L/kg/hr, the fraction eliminated unchanged in the urine was 83% +/- 16%, and the apparent volume of distribution (Vdss) was 1.33 +/- 0.53 L/kg. The bioavailability determined from comparison of intravenous and oral area under the curve data was 71% +/- 27%. Results of this study support an initial famotidine dose of 20 mg intravenously or 40 mg orally every 12 hours in patients with CF who are older than 9 years of age.

Renal excretion of famotidine and role of adenosine in renal failure induced by bacterial lipopolysaccharide in rats.

Our previous studies have reported that bacterial lipopolysaccharide (LPS) dramatically changes the ability of the active tubular anion secretory system in rats. The present study has investigated the effects of LPS on the pharmacokinetics and renal handling of famotidine, an organic cation drug excreted primarily by an active tubular secretion mechanism in rats. The role of adenosine in the LPS-induced renal failure was also investigated using theophylline, an adenosine antagonist. Pretreatment with LPS (250 micrograms/kg) significantly decreased the steady-state volume of distribution, systemic clearance, and renal clearance (CLr) of famotidine, but not nonrenal clearance. No significant differences in total urinary recovery of unchanged famotidine were observed between treatments. Pretreatment with LPS significantly decreased the glomerular filtration rate (GFR), estimated as inulin clearance. LPS increased the clearance ratio of famotidine (CLr/GFR), but not the net tubular secretion, indicating that LPS has little or no effect on the active tubular cation secretory system. Theophylline (10 mg/kg) improved LPS-induced decrease in GFR without causing any changes in the pharmacokinetic parameters of famotidine. These findings provide further evidence that LPS produces different effects on the distribution and the active tubular secretory systems of anion and cation drugs, and that adenosine may play an important role in the induction of renal failure by LPS.

Does smoking influence the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine?

Twelve healthy habitual cigarette smokers and eight non-smokers participated in a double-blind placebo controlled study to determine the effect of smoking on the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine. In smokers, cigarette smoking was standardised and started 1 h before (A), or 2 h after (B) drug administration, or was prohibited (C). Intragastric pH-levels (IGpH) were measured with an ambulatory pH-recorder. Famotidine (40 mg orally) significantly raised median 22 h IGpH in non-smokers and smokers in all study periods. The smoking sequence (A, B, C) did not significantly influence median 22 h IGpH in both placebo-treated and famotidine-treated smokers, and no significant difference in median 22 h IGpH was shown between smokers and non-smokers. Plasma drug concentrations were similar in the various experiments, although famotidine was detected earlier in plasma from non-smokers compared with smokers (P less than 0.05). Smoking did not interfere significantly with the pharmacokinetics and pharmacodynamics of famotidine.

[Time of famotidine administration and healing of duodenal ulcer: is 18.00 o'clock of importance?]. / Einnahmezeitpunkt von Famotidin und Heilung des Ulcus duodeni: Ist 18.00 Uhr von Bedeutung?

In a double-blind, placebo-controlled two centre trial, the effect of a 40 mg oral dose of famotidine administered at 6 p.m. to the same dose given at 10:00 p.m. was studied in 38 patients with duodenal ulcers. After 2 weeks 61% of the ulcers had healed; this had risen to 89% by the end of week 4. The statistically non-significant trend to better results following administration later at night (which apparently contradicts other published results) may have been due to a delay in adsorption caused by food ingestion and the related nocturnal pH levels.

Famotidine. Pharmacokinetic properties and suppression of acid secretion in paediatric patients following cardiac surgery.

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.

Famotidine. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in peptic ulcer disease and other allied diseases.

Famotidine is a highly selective histamine H2-receptor antagonist. In healthy volunteers and patients with acid hypersecretory disease it is approximately 20 to 50 times more potent at inhibiting gastric acid secretion than cimetidine and 8 times more potent than ranitidine on a weight basis. As shown in placebo-controlled trials, famotidine is effective in healing both duodenal and gastric ulcers. Famotidine 20mg twice daily or 40mg at bedtime achieves healing rates and symptom relief similar or superior to those achieved by cimetidine 800mg daily or ranitidine 300mg daily in patients with peptic ulcer disease. Results of 1 placebo-controlled study suggest that famotidine prevents recurrence of duodenal ulcer, but comparative trials are needed to establish its relative efficacy in maintenance therapy. The few non-comparative trials conducted to date also suggest that famotidine 10 to 20mg twice daily may be effective in the treatment of gastritis and reflux gastro-oesophagitis. In comparative trials, famotidine was similar in efficacy to cimetidine in the treatment of upper gastrointestinal bleeding and to ranitidine in the prevention of pulmonary aspiration of acid. In patients with Zollinger-Ellison syndrome, the potency and long duration of action of famotidine may confer an advantage over other H2-receptor antagonists--in individualised doses (mean 0.33 g/day) famotidine successfully controlled acid secretion for up to 72 months in 1 study of such patients. Accumulated clinical evidence confirms that famotidine is very well tolerated and is free of the antiandrogenic effects infrequently reported with cimetidine. Moreover, famotidine is not associated with altered hepatic metabolism of drugs. Thus, famotidine is an effective, well-tolerated alternative to cimetidine and ranitidine. Famotidine is also promising as maintenance therapy for preventing recurrence of duodenal ulcer and as initial or maintenance treatment of gastric hypersecretory disorders, but further clinical experience, particularly in the long term, is needed to define the relative efficacy and tolerability of famotidine in these indications.