Glutaraldehyde-crosslinked chitosan-polyethylene oxide nanofibers as a potential gastroretentive delivery system of nizatidine for augmented gastroprotective activity.

Nizatidine (NIZ), a histamine H2-receptor antagonist, is soluble and stable in the stomach, however, it exhibits a short half-life and a rapid clearance. Therefore, chitosan (CS) and polyethylene oxide (PEO) nanofibers (NFs) at different weight ratios were prepared by electrospinning and characterized. The selected uncrosslinked and glutaraldehyde-crosslinked NFs were investigated regarding floating, solid-state characteristics, in vitro release, and in vitro cytotoxicity. The cytoprotective activity against ethanol-induced gastric injury in rats was evaluated through macroscopical, histopathological, immunohistochemical, and oxidative stress examinations. NFs based on 8:2 CS:PEO exhibited the smallest diameter (119.17 ± 22.05 nm) and the greatest mucoadhesion (22.82 ± 3.21 g/cm2), so they were crosslinked with glutaraldehyde. Solid-state characterization indicated polymers interaction, a successful crosslinking, and NIZ dispersion in NFs. Crosslinking maintained swollen mats at pH 1.2 (swelling% = 29.47 ± 3.50% at 24 h), retarded their erosion at pH 6.8 (swelling%= 84.64 ± 4.91% vs. 25.40 ± 0.79% for the uncrosslinked NFs at 24 h), augmented the floating up to 24 h vs. 10 min for the uncrosslinked NFs at pH 1.2 and prolonged the drug release (%drug released ≥ 93% at 24 h vs. 4 and 5 h for the uncrosslinked NFs at pHs 1.2 and 6.8, respectively). The viability of Caco-2 cells ≥ 86.87 ± 6.86% revealed NFs biocompatibility and unreacted glutaraldehyde removal. Crosslinking of 8:2 CS:PEO NFs potentiated the antiulcer activity (38.98 vs. 8.67 for the uncrosslinked NFs) as well as it preserved the gastric wall architecture, COX-2 expression, and oxidative stress markers levels of the normal rats.

Formulation, optimization, and evaluation of raft-forming formulations containing Nizatidine.

OBJECTIVE: The main objective of this research is to formulate, optimize, and evaluate raft-forming chewable tablets of Nizatidine. Various raft-forming agents were used in preliminary screening. Sodium alginate showed maximum raft strength, so tablets were prepared using sodium alginate as the raft forming agent, along with calcium carbonate (CaCO3) as antacid and raft strengthening agent, and sodium bicarbonate (NaHCO3) as a gas generating agent. RESEARCH DESIGN AND METHODS: Raft forming chewable tablets containing Nizatidine were prepared by direct compression and wet granulation methods, and evaluated for drug content, acid neutralization capacity, raft strength, and in-vitro drug release in 0.1 N HCl. Box-Behnken design was used for optimization. RESULTS: Two optimized formulations were predicted from the design space. The first optimized recommended concentrations of the independent variables were predicted to be X1 = 275.92 mg, X2 = 28.60 mg, and X3 = 202.14 mg for direct compression technique and the second optimized recommended concentrations were predicted to be X1 = 253.62 mg, X2 = 24.60 mg, and X3 = 201.77 mg for wet granulation technique. Optimized formulations were stable at accelerated environmental testing for six months at 35 °C and 45 °C with 75% relative humidity. X-Ray showed that the raft floated immediately after ingestion and remained intact for ∼3 h. CONCLUSION: Raft was successfully formed and optimized. Upon chewing tablets, a raft is formed on stomach content. That results in rapid relief of acid burning symptoms and delivering the drug into systemic circulation with enhanced bioavailability.

Radioiodination and biological evaluation of nizatidine as a new highly selective radiotracer for peptic ulcer disorder detection.

Nizatidine has been labeled using [125 I] with chloramine-T as oxidizing agent. Factors such as the amount of oxidizing agent, amount of substrate, pH, reaction temperature, and reaction time have been systematically studied to optimize the iodination. Biodistribution studies indicate the suitability of radioiodinated nizatidine as a novel tracer to image stomach ulcer. Radioiodinated nizatidine may be considered a highly selective radiotracer for peptic ulcer imaging.

An Efficient Ion-Pair Liquid Chromatographic Method for the Determination of Some H2 Receptor Antagonists.

A simple, efficient and reliable ion-pair chromatography (IPC) method was developed and validated for the determination of some H2 receptor antagonists including ranitidine (RAN), nizatidine (NIZ) and famotidine (FAM). The use of IPC separations provided improved peak resolution with good peak shape in short analysis time and augmented method selectivity compared with the frequently used RP-C18 methods. A simple isocratic mode with mobile phase containing acetonitrile and 20 mM acetate buffer (50 : 50, v/v) containing 20 mM sodium dodecyl sulfate was used for separation. The flow rate was set at 1.0 mL min(-1), and the effluent was monitored by UV detector at 280 nm FAM and 320 nm for NIZ and RAN. The method was validated in accordance with International Conference on Harmonization guidelines and shown to be suitable for intended applications. The limits of detections and quantitations were 0.008-0.011 and 0.025-0.033 µg mL(-1), respectively. The proposed IPC method was successfully applied for the determination of pharmaceutical dosage forms without prior need for separation. Additionally, the developed method was applied for the determination of RAN in rabbit plasma using NIZ as the internal standard. The method entailed direct injection of the plasma samples after deproteination using methanol. Finally, the proposed IPC method was applied successfully in a pharmacokinetic study for RAN in rabbits after a single oral dose of RAN.

Development and validation of a sensitive LC-MS/MS assay for the quantification of nizatidine in human plasma and urine and its application to pharmacokinetic study.

We developed and validated a high performance liquid chromatographic method coupled with triple quadrupole mass spectrometry for analysis of nizatidine in human plasma and urine. The biological samples were precipitated with methanol before separation on an Agilent Eclipse Plus C18 column (100mm×46mm, 5µm) with a mixture of methanol and water (95:5, plus 5mM ammonium formate) as the mobile phase at 0.5mL/min. Detection was performed using multiple reaction monitoring modes via electrospray ionization (ESI) at m/z 332.1→155.1 (for nizatidine) and m/z 335.1→155.1 (for [(2)H3]-nizatidine, the internal standard). The linear response range was 5-2000ng/mL and 0.5-80µg/mL for human plasma and urine, with the lower limits of quantification of 5ng/mL and 0.5µg/mL, respectively. The method was validated according to the biological method validation guidelines of the Food and Drug Administration and proved acceptable. This newly developed analytical method was successfully applied in a pharmacokinetic study following single oral administration of a 150mg nizatidine capsule in to 16 healthy Chinese subjects. Maximum and endpoint concentrations in plasma and urine were quantifiable, suggesting our method is appropriate for routine pharmacokinetic analysis.

Formulation and characterization of floating microballoons of nizatidine for effective treatment of gastric ulcers in murine model.

BACKGROUND: The purpose of the present study was to formulate and characterize Nizatidine-encapsulated microballoons for enhancing bioavailability and increasing the residence time of drug in the gastrointestinal tract. METHODS: Microballoons were prepared using emulsion solvent diffusion method using Eudragit S-100 and HPMC as the polymer. The formulation process was optimized for polymer ratio, drug: polymer ratio, emulsifier concentration, stirring speed, stirring time. Optimized formulation was subjected to scanning electron microscopy, drug entrapment, buoyancy studies, in-vitro drug release and in-vivo floating efficiency (X-ray) study. In-vivo antiulcer activity was assessed by ethanol-induced ulcer in murine model. RESULTS: The microballoons were smooth and spherical in shape and were porous in nature due to hollow core. A sustained release of drug was observed for 12 h. Examination of the sequential X-ray images taken during the study clearly indicated that the optimized formulation remained buoyant and uniformly distributed in the gastric contents for a period of 12 h. In ethanol-induced ulcer model, drug-loaded Microballoon-treated group showed significant (p < 0.01) ulcer protection index as compared to free drug-treated group. CONCLUSION: Nizatidine-loaded floating microballoons may serve as a useful drug delivery system for prolonging the gastric residence time and effective treatment of gastric ulcers.

HPLC fluorescence method for the determination of nizatidine in human plasma and its application to pharmacokinetic study.

A sensitive high-performance liquid chromatographic (HPLC) method was developed for the determination of nizatidine in human plasma. Nizatidine was derivatized by 4-fluoro-7-nitrobenzofurazan (NBD-F). Chromatographic separation was performed on a Inertsil C18 column (150 mm × 4.6 mm, 5 µm) using isocratic elution by a mobile phase consisting of methanol/water (55:45) at a flow rate of 1.2 mL/min. Amlodipine was used as the internal standard (IS). Fluorescence detector was used operated at 461 nm (excitation) and 517 nm (emission), respectively. The calibration curve was linear over the range of 50-2000 ng/mL. This method was successfully applied to a pharmacokinetic study after oral administration of a dose (150 mg) of nizatidine.

Pharmacokinetics of ranitidine and nizatidine in very elderly patients.

This study was undertaken to examine whether the pharmacokinetic profiles of ranitidine and nizatidine, the H2 antagonists, differed with repeated doses in very elderly patients (>80 years old). Ranitidine (150 mg) or nizatidine (150 mg) was given twice daily in 10 very elderly female patients for 14 days. This study was a randomized, crossover design with a wash-out period of 14 days. Pharmacokinetic profiles were determined after first (on day 1) and 27th (on day 14) doses of each agent. The maximum plasma drug concentration (Cmax) and area under the plasma drug concentration-time curve (AUC) were significantly greater after the 27th than after the first dose in the ranitidine but not in the nizatidine trials. The accumulation of ranitidine in plasma tended to be greater than that of nizatidine. These results suggest that nizatidine is safer for the repeated treatment in very elderly patients.

Bioequivalence of two oral formulations of nizatidine capsules in healthy male volunteers.

PURPOSE: The purpose of this randomized, crossover study was to compare the bioavailability of a generic and an innovator formulation of nizatidine 300 mg capsules under fasting conditions. METHODS: Twenty blood samples per period were collected from 20 healthy, Arab male volunteers over 16 h, plasma nizatidine concentrations were determined by HPLC assay, and pharmacokinetic parameters were determined by the non-compartmental method. RESULTS: Mean+/-SD C(max), T(max), AUC(0-->t), AUC(0-->infinity), and t1/2 were 2.96+/-0.54 and 3.28+/-0.68 microg/ml, 1.31+/-0.70 and 0.93+/-0.38 h, 9.04+/-1.66 and 9.03+/-1.94 microg x h/ml, 9.17+/-1.64 and 9.12+/-1.94 microg x h/ml, and 1.64+/-0.21 and 1.58+/-0.22 h for the generic and innovator formulation, respectively. The parametric 90% confidence intervals on the mean of the difference between log-transformed values were 98.06% to 103.21%, 98.74% to 103.71%, and 83.37% to 101.34%, for AUC(0-->t), AUC(0-->infinity), and C(max), respectively. CONCLUSION: The results indicate that these two formulations are equivalent in the rate and extent of absorption.

Developmental pharmacokinetics and pharmacodynamics of nizatidine.

OBJECTIVES: To characterize the impact of development on the pharmacokinetics and pharmacodynamics of nizatidine. METHODS: Children (age range, 5 days-18 years) and adults (age range, 18-50 years) were enrolled in four open-label trials. Nizatidine formulation and dose were determined by age: infants received 2 or 4 mg/kg i.v., children 2.5 or 5 mg/kg in one of three oral liquid formulations, and adolescents and adults received a fixed 150-mg capsule. Nizatidine and N-desmethylnizatidine concentrations were measured in serial post-dose plasma samples by a high-performance liquid chromatographic assay with mass spectrometric detection. Intragastric pH was recorded during a 24-hour post-dose interval. RESULTS: Data on 93 subjects were combined with previous values from 36 individuals to cover an age group not adequately captured and to control for formulation effects. Dose-normalized exposure estimates revealed no apparent age dependence; however, maximum plasma concentration (298.5 +/- 100.7 v 552.8 +/- 152.4 ng/mL per mg/kg dose) and AUC0-infinity (954.4 +/- 379.8 v 1,573.0 +/- 347.4 ng*hour/mL per mg/kg dose) were reduced in extemporaneous formulations in apple juice. The apparent modest age dependence observed for total body clearance (Cl/F) (r = 0.365) and Vss/F (r = 0.221) reflected a formulation-dependent decrease in bioavailability rather than a true age effect. The age-associated changes in lambda z observed for nizatidine and its metabolite were predictable and consistent with developmental acquisition of renal function. Mean and median pH, as well as fraction of time that the dosing interval remained above target pH values, were significantly greater with administration of the drug than without. CONCLUSIONS: The biodisposition of nizatidine in children and adults is similar; however, response after a comparable weight-based dose is equal and potentially greater in children.

The bioequivalence of nizatidine (Axid) in two extemporaneously and one commercially prepared oral liquid formulations compared with capsule.

Nizatidine (Axid) is an H2-receptor antagonist used for the treatment of acid-related gastrointestinal disorders. Given the frequency of these conditions in children and the potential for pediatric use of nizatidine, an oral liquid dosage formulation would provide an alternative treatment option for patients unable to swallow solid oral dosage forms. This study was designed as an open-label, single-dose, four-way crossover trial to investigate the bioequivalence of 150 mg nizatidine administered in three oral liquid formulations (a commercially prepared oral syrup, an extemporaneous solution in apple juice, and an extemporaneous suspension in infant formula) relative to the marketed capsule formulation. Twenty-four adult subjects (ages 31.2 +/- 7.5 years; weight 71.1 +/- 11.8 kg) were enrolled, and blood samples for determination of plasma nizatidine concentrations were collected prior to drug administration and at 19 discrete intervals over a 24-hour postdose interval. Nizatidine was quantitated from plasma using a validated HPLC-MS assay, and a noncompartmental approach was used to describe nizatidine biodisposition in all subjects. Significant treatment effects were observed for log-normalized Cmax, AUC0-n, and AUC0-infinity (p < 0.001). Further evaluation revealed that nizatidine prepared in apple juice was markedly less bioavailable than the reference capsule, with 90% confidence intervals (CIs) of 0.518-0.626, 0.682-0.751, and 0.696-0.763 for Cmax, AUC0-n, and AUC0-infinity, respectively. The remaining two oral formulations demonstrated 90% CI within the guidelines established by the Food and Drug Administration (e.g., 0.80-1.25). Thus, nizatidine in infant formula and the commercially prepared oral syrup can be considered bioequivalent to the reference capsule.

Pharmacokinetics and pharmacodynamics of a novel nizatidine controlled-release formulation in healthy subjects.

The pharmacokinetics and intragastric pH effects of a novel nizatidine controlled-release (CR) formulation were compared to a currently marketed immediate-release (IR) nizatidine formulation (Axid). The bimodal pulsatile release characteristics of nizatidine CR decreased its Cmax by approximately 42% compared to nizatidine IR while maintaining 90% relative bioavailability; tmax was approximately 1.6 times longer with the CR formulation. These characteristics enabled controlled-release nizatidine to sustain effective plasma drug concentrations for a greater duration than immediate-release nizatidine over the dosing intervals. In multiple doses, the 24-hour AUC ratio for all comparisons of nizatidine CR 150 mg bid, nizatidine CR 300 mg daily, and nizatidine IR 150 mg bid was between 97% and 99%. Mean pH AUC values for nizatidine CR 150 mg bid and nizatidine IR 150 mg bid were similar overall during the 0- to 14-hour and 14- to 24-hour dosing intervals. For the 14- to 24-hour dosing interval, nizatidine CR 150 mg maintained gastric pH over 3.0 and 4.0 for 42% and 27% of the time compared to 39% and 23% for nizatidine IR, respectively. Nizatidine CR 300 mg, compared to the 150-mg CR and IR regimens, had a greater effect on increasing evening intragastric pH, thus providing support for the potential utility of nizatidine CR 300 mg dosed at night in alleviating nocturnal symptoms of gastroesophageal reflux disease.

Lack of effect of nizatidine-induced elevation of gastric pH on the oral bioavailability of dapsone in healthy volunteers.

STUDY OBJECTIVE: To investigate the effect of histamine2 (H2)-receptor antagonist-induced elevation of gastric pH on oral bioavailability of a single dose of dapsone 100 mg. DESIGN: Prospective, randomized, crossover, open-label, single-dose pharmacokinetic study. SETTING: Teaching hospital. PATIENTS: Sixteen men were enrolled in the study; data from 11 subjects were evaluable. INTERVENTIONS: Participants received two treatments separated by at least 14 days. Treatment A consisted of a single dose of dapsone 100 mg. Treatment B consisted of a single dose of dapsone 100 mg plus two doses of oral nizatidine 300 mg administered 3-4 hours apart to maintain gastric pH above 6.0. Plasma samples collected before and up to 120 hours after dapsone administration were analyzed for dapsone and monoacetyldapsone (MADDS) by high-performance liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental analysis. MEASUREMENTS AND MAIN RESULTS: Gastric pH in the first 6 hours after dapsone administration was above 6.0 for a mean +/- SD of 1.1% +/- 2.9% of the time in the absence of nizatidine and 69.5% +/- 18.0% of the time during nizatidine therapy. The geometric mean dapsone maximum plasma concentration (Cmax) declined by 13% (p<0.01), and median time to Cmax occurred 2 hours later (p<0.01) with nizatidine coadministration compared with dapsone alone. Inclusion of the 90% confidence interval for the mean Cmax ratio within the equivalence interval of 0.8-1.25 demonstrated the lack of clinical significance for this modest decrease in Cmax. Neither the area under the dapsone plasma concentration-time curve from zero to infinity nor the elimination half-life of dapsone were significantly altered by nizatidine. No clinically significant changes were observed in the pharmacokinetics of MADDS with regard to coadministration of nizatidine. CONCLUSION: Elevation of gastric pH by H2-receptor antagonists, such as nizatidine, does not result in clinically important changes in the rate or extent of oral dapsone absorption.

Single-dose pharmacokinetics of nizatidine (Axid) in children.

The pharmacokinetics of nizatidine following a single 5.0 mg/kg oral dose given as an extemporaneous liquid formulation in apple juice was examined in 12 healthy children (8.0 +/- 2.4 years, 30.7 +/- 8.4 kg). Nizatidine and N-desmethylnizatidine were quantitated by HPLC/MS from five post dose blood samples taken over a 12-hour period. The apparent terminal elimination rate constant for nizatidine in the pediatric subjects (0.58 +/- 0.8h(-1)) was virtually identical to that (0.54 +/- 0.13 h(-1)) previously reported from adult studies. When corrected for an estimated 30% reduction in nizatidine oral bioavailability observed in adults upon coingestion of the drug with other fruit/vegetable juices, nizatidine pharmacokinetic parameter estimates (e.g., Cmax, CL/F, Vss/F) in our pediatric subjects were similar to those previously reported in adults who were administered dimensionally similar (e.g., approximately 4 mg/kg) solid oral doses of the drug. Examination of the mean area under the curve (i.e., AUC0-infinity for nizatidine and N-desmethylnizatidine suggested an approximate 15% metabolic conversion of the parent drug. Finally, nizatidine plasma concentrations in pediatric patients following a single 5.0 mg/kg oral dose exceeded the EC50 value of the drug for gastric acid suppression determined from adult studies for approximately 6 hours.

Pharmacokinetic optimisation in the treatment of gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease (GORD) is a very common disorder of upper gastro-intestinal motility, differing widely in severity and prognosis. Medical therapy of GORD has involved antacids, alginates, prokinetic agents and antisecretory compounds, primarily H2 receptor antagonists and proton pump inhibitors. Knowledge of the pharmacokinetics of these compounds is important, to optimise the therapeutic benefit in each patient. GORD patients are often elderly and pharmacokinetics are move variable in this group. Furthermore, they often suffer from other diseases needing medical therapy and may need a combination of drugs to heal reflux oesophagitis and relieve reflux symptoms. The ideal therapy for GORD will have linear pharmacokinetics, a relatively long plasma half-life (t1/2), a duration of action allowing once daily administration, and a stable effect independent of interactions with food, antacids and other drugs. Over-the-counter antacids and alginates are widely used, buy may affect absorption of H2 receptor antagonists like cimetidine and ranitidine. Aluminium-containing antacids may, over time, cause toxicity in patients with renal insufficiency. In the treatment of GORD, cisapride presents important advantages over earlier prokinetic compounds, with a longer plasma t1/2, low penetration of the blood-brain barrier and fewer adverse effects. The group of H2 receptor antagonists is still the most frequently use therapy for GORD. Linear pharmacokinetics make dose adjustments easy and safe. In individual patients, suppression of gastric secretion is related to the area under the plasma concentration-time curve (AUC), but there is wide interindividual variation in the effect of the same oral dose. Only with frequent administration and high doses will acid suppression approximate that of proton pump inhibitors. Tolerance, with loss of effect over time, however, is most pronounced in this situation. H2 receptor antagonists seem well suited for on-demand treatment of reflux symptoms, due to the rapid onset of effect and a decrease likelihood of the development of tolerance. Effervescent formulations provide more rapid absorption and almost immediate clinical effect. Cimetidine, however, causes interference with the metabolism of several other drugs in common use. In elderly patients elimination is delayed and in patients with renal insufficiency, dose reductions of all H2 receptor antagonists are recommended. The most effective medical therapy for any severity of GORD, particularly in severe oesophagitis, are the proton pump inhibitors. The substituted benzimidazoles (omeprazole, lansoprazole and pantoprazole), are prodrugs which once trapped and activated in the acid milieu of the gastric glands potently suppress gastric secretion of acid and pepsin. Their long duration of action, more related to the slow turnover of parietal cell H(+)-K+ ATPase molecules, allows once daily administration in most patients. Interindividual variation in bioavailability sometimes calls for higher doses or twice daily administration. Acid suppression is closely related to the AUC. Omeprazole is prone to interaction with the metabolism of other drugs, some of which may e be clinically important. Lansoprazole seems to have an earlier onset of action than omeprazole, ascribed to higher bioavailability during the first days of treatment. Proton pump inhibitors have a slow onset of action, which makes them unsuited for on-demand therapy. Clinical practice in GORD calls for the use of not one but several substances, according to the severity and symptom pattern of the patient. Pharmacokinetic optimisation in the treatment of GORD is a question of selecting the most suitable substances and administration schemes within each group. Cisapride is superior to other prokinetics in terms of longer plasma t1/2 and less toxicity. Amongst H2 receptor antagonists, the more long-acting compounds, ranitidine and famotidine, will improve acidity control througho

Diurnal variation in the pharmacokinetics of nizatidine in healthy volunteers and in patients with peptic ulcer disease.

Six healthy volunteers and six patients with asymptomatic duodenal ulcer disease received placebo or 300 mg nizatidine once at night or twice daily (morning and evening) for a week in a random, cross-over fashion. Steady-state serum nizatidine concentrations and gastric pH were measured over a 24-hour period. No significant differences in the pharmacokinetic indices were observed between the healthy volunteers and patients with duodenal ulcer disease. In patients with duodenal ulcers, significantly lower peak serum concentrations, longer half-life (t1/2) and larger volume of distribution (Vd) were observed after the night doses compared with the daytime doses. The diurnal variation in drug kinetics between the nighttime and daytime doses in the twice daily regimen may be caused by a slower absorption rate, paralleled with a higher extent of distribution. Despite lower serum nizatidine concentrations, gastric pH was higher in the evening than in the daytime; it is speculated that this was due to a time-dependent enhanced distribution of the H2-receptor blocker into the site of action.

Carrier-mediated active transport of histamine H2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepatocytes: contribution of type I system.

The uptake rates of [3H]cimetidine and [14C]nizatidine into isolated rat hepatocytes were studied in order to identify the transport mechanism of histamine H2 receptor antagonists into the liver. In addition, the contributions of the uptake clearance to hepatic clearance for both drugs also were estimated. The uptakes of cimetidine and nizatidine achieved equilibrium in 5 min with cell-to-medium concentration ratios of 12.0 and 3.5, respectively. The uptake systems of both histamine H2 antagonists consisted of a saturable component and a nonsaturable component. The contributions of the carrier-mediated transport system for cimetidine and nizatidine at therapeutic concentrations (3 microM) were 86 and 70%, respectively. The uptakes of both drugs showed temperature dependency and were decreased significantly by various metabolic inhibitors and a sulfhydryl group modifying reagent. Only a slight effect was seen in the replacement of sodium with lithium on both uptakes. The uptake of cimetidine was reduced markedly in parallel with the reduction in the cellular ATP level and was inhibited by other histamine H2 antagonists and various organic cations. Furthermore, both nizatidine and quinidine competitively inhibited cimetidine's uptake. These results demonstrate that cimetidine and nizatidine are taken up into hepatocytes by a common Na(+)-independent transport system, namely the type I organic cation uptake system. By comparing the in vitro hepatic uptake clearance obtained from this study and the in vivo hepatic clearance from pharmacokinetic data, it is suggested that the rate-limiting step in hepatic clearance for cimetidine is drug metabolism, whereas for nizatidine, it is the uptake process.

Short report: a comparative study of the interaction between antacid and H2-receptor antagonists.

The influence of concomitant antacid administration on the relative bioavailability of the H2-receptor antagonists cimetidine, famotidine, nizatidine and ranitidine, was investigated in a panel of 21 healthy, adult male volunteers in an eight-way crossover trial. Administration with antacid reduced the bioavailability of all agents tested. The reduction in area under the serum concentration-time curve (AUC) was greatest for cimetidine (23%) and ranitidine (26%) and least for nizatidine (12%) and famotidine (19%). Reductions in peak serum concentration (Cmax) followed a similar pattern. The times of peak serum concentrations were not affected by antacid. Comparison of the relative bioavailability among all drugs tested showed no statistically significant differences in the effect of antacid administration on these agents. However, a high degree of intersubject variability was observed.

Drug interactions of H2-receptor antagonists.

Three drug interactions of nizatidine and of other antisecretory agents were studied comparatively. First, the effects of nizatidine, cimetidine and ranitidine on the dispositional kinetics of theophylline were evaluated in chronic obstructive pulmonary disease (COPD) patients. Second, the effect of magnesium/aluminium hydroxide on the relative bioavailability of nizatidine, famotidine, cimetidine and ranitidine was evaluated in healthy volunteers. Finally, the effects of nizatidine and omeprazole on the dispositional kinetics of phenytoin were evaluated in healthy volunteers. Only cimetidine altered the steady-state kinetics of oral theophylline, slowing theophylline clearance by 25%. Each of the H2-receptor antagonists exhibited a modest decline in relative bioavailability when ingested with antacid. Antacid ingestion decreased the bioavailability of famotidine, ranitidine and cimetidine by 20-25%, and the bioavailability of nizatidine by 12%. Each of these effects was statistically significant. Finally, it was found that neither omeprazole nor nizatidine affected the single dose kinetics of phenytoin.

Pharmacokinetics of nizatidine in dogs and rats.

1. Plasma levels of nizatidine and two metabolites (N-desmethyl nizatidine and nizatidine S-oxide) were studied in dogs and rats. 2. The time-courses of plasma concentration of nizatidine after i.v. and oral administration to dogs well fitted a two-compartment model. Absorption after oral administration was rapid, and the peak plasma level (Cmax) and area under the plasma concentration-time curve (AUC) were proportional to doses. Absolute bioavailability was close to 100%, indicating that nizatidine has a negligible first-pass effect. 3. Nizatidine was eliminated by apparent first-order kinetics after i.v. administration to rats, and the elimination in rats was faster than in dogs. Bioavailability in rats was 72.4%, indicating a slight first-pass effect in rats. 4. When plasma clearance (Clp), or volume of distribution (Vd.beta), of nizatidine were plotted against animal body weight on a log-log scale, good correlations were obtained for rats, dogs and humans. 5. Peak levels (Cmax) of two metabolites were reached at 0.5-1.0 h after oral and i.v. administration of nizatidine to dogs. The elimination curves of the two metabolites were similar to that of nizatidine. Significant relationships were found between doses of nizatidine and Cmax or AUC of both metabolites.