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Importance: A publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies., Objective: To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels., Design, Setting, and Participants: One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 μmol/L) to higher concentrations (10 000 μmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method., Main Outcomes and Measures: NDMA detected in simulated gastric fluid 2 hours after adding ranitidine., Results: At a supraphysiologic nitrite concentration (ie, 10 000 μmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 μmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 μmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 μmol/L) or 10-fold physiologic (1000 μmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 μmol/L)., Conclusions and Relevance: In this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 μmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.

Biocompatible and luminescent nanostructures synthesized by capping gold-carbon nanoparticles (HOOC-4-C 6 H 4 -AuNPs) with amino acids tyrosine, tryptophan, and cysteine were used for the quantitative estimation of ranitidine (RNH), a peptic ulcer and gastroesophageal reflux drug. We applied a fluorescence quenching mechanism to investigate the viability of the energy transfer based on gold-carbon nanosensors. Förster resonance energy transfer (FRET) calculations showed a donor-acceptor distance of 1.69 nm (Tyr@AuNPs), 2.27 nm (Trp@AuNPs), and 2.32 nm (Cys@AuNPs). The constant time-resolved fluorescence lifetime measurements supported the static quenching nature. This method was successfully utilized in the detection and quantification of RNH, with a limit of detection (LOD) of 0.174, 0.56, and 0.332 μM for Tyr@AuNP, Trp@AuNP, and Cys@AuNP bioconjugates, respectively. This approach was also successful in the quantification of RNH in spiked serum samples.

Trospium chloride, a muscarinic receptor blocker, is poorly absorbed with different rates from areas in the jejunum and the cecum/ascending colon. To evaluate whether organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion (MATE) 1 and MATE2-K are involved in pharmacokinetics, competitions with ranitidine, a probe inhibitor of the cation transporters, were evaluated in transfected HEK293 cells. Furthermore, a drug interaction study with trospium chloride after intravenous (2 mg) and oral dosing (30 mg) plus ranitidine (300 mg) was performed in 12 healthy subjects and evaluated by noncompartmental analysis and population pharmacokinetic modeling. Ranitidine inhibited OCT1, OCT2, MATE1, and MATE2-K with half maximal inhibitory concentration values of 186 ± 25 µM, 482 ± 105 µM, 134 ± 37 µM, and 35 ± 11 µM, respectively. In contrast to our hypothesis, coadministration of ranitidine did not significantly decrease oral absorption of trospium. Instead, renal clearance was lowered by ∼15% (530 ± 99 vs 460 ± 120 mL/min; P < .05). It is possible that ranitidine was not available in competitive concentrations at the major colonic absorption site, as the inhibitor is absorbed in the small intestine and undergoes degradation by microbiota. The renal effects apparently result from inhibition of MATE1 and/or MATE2-K by ranitidine as predicted by in vitro to in vivo extrapolation. However, all pharmacokinetic changes were not of clinical relevance for the drug with highly variable pharmacokinetics. Intravenous trospium significantly lowered mean absorption time and relative bioavailability of ranitidine, which was most likely caused by muscarinic receptor blocking effects on intestinal motility and water turnover., (© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

A novel liquid-liquid-solid membrane microextraction (LLSMME) method which integrates hollow fiber liquid phase microextraction (HF-LPME) and solid phase microextraction (SPME) was developed for bio-sample preparation. The homogeneous zeolitic imidazolate framework 8 mixed matrix membrane (ZIF-8-MMM) was prepared by in situ self-assembly of ZIF-8 on the inner surface of hollow fiber membrane and employed as a flexible LLSMME device. Incorporating the advantages of both HF-LPME and SPME, the as-fabricated ZIF-8-MMM exhibited excellent performance on the extraction and preconcentration of small molecule drugs of different polarity from complex biological matrices. As a case study, ZIF-8-MMM-based LLSMME coupled with UPLC-MS/MS were developed and validated for determination of ibuprofen, simvastatin and ranitidine at trace levels in rat plasma. The method showed good linearity (r 2  > 0.99) and repeatability (RSD < 15%), low limits of detection (2-3 ng mL -1 ) and high relative recoveries (97.42-103.8%). The enrichment factors were between 87.3 and 112.6. Our study provided a promising strategy for developing more efficient, cost-effective and environmentally friendly technique for bio-sample pretreatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex-dependent manner. As ranitidine is a substrate for the efflux transporter P-glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (p<0.05) the bioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (p<0.05), and to a greater extent in males, but had no influence on the bioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The use of anti-ulcer medications, such as cimetidine, ranitidine, and omeprazole, is common in performance horses. The use of these drugs is regulated in performance horses, and as such a withdrawal time is necessary prior to competition to avoid a medication violation. To the authors' knowledge, there are no reports in the literature describing repeated oral administrations of these drugs in the horse to determine a regulatory threshold and related withdrawal time recommendations. Therefore, the objective of the current study was to describe the disposition and elimination pharmacokinetics of these anti-ulcer medications following oral administration to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 20 mg/kg BID of cimetidine or 8 mg/kg BID of ranitidine, both for seven doses or 2.28 g of omeprazole SID for four doses. Blood samples were collected, serum drug concentrations were determined, and elimination pharmacokinetic parameters were calculated. The serum elimination half-life was 7.05 ± 1.02, 7.43 ± 0.851 and 3.94 ± 1.04 h for cimetidine, ranitidine, and omeprazole, respectively. Serum cimetidine and ranitidine concentrations were above the LOQ and omeprazole and omeprazole sulfide below the LOQ in all horses studied upon termination of sample collection., (© 2016 John Wiley & Sons Ltd.)

Background: The aim of this study was to determine the effect of gestational age on pharmacokinetics of ranitidine in newborns with gastroesophageal reflux., Methods: A prospective, descriptive and pharmacokinetic study was carried out in 30 pre-term and 20 full-term babies. 3 mg/kg of ranitidine was administered intravenously to all the babies and at 0.25, 0.5, 1, 2, 4, and 8 h following the administration, samples of blood were drawn to assess ranitidine levels using high performance liquid chromatographic technique., Results: Pharmacokinetics of ranitidine had a bi-exponential behavior with a half-life elimination of (t1/2el) 2.79 h, area under curve (AUC) of 1688 ng/mL, volume of distribution (Vd) of 1.44 L/kg, and clearance (Cl) of 5.9 L/kg/h. The median plasmatic concentration in pre-terms was 1113 ng/mL and 280 ng/mL in full-terms. Vd, t1/2 and Cl presented high values in preterm although the correlation of Cl with glomerular filtration in term newborns was better., Conclusions: Plasma levels of ranitidine depend on the gestational age of the newborns. However, the possible relationship between after-birth age and pharmacokinetics of the neonates as their internal organs get matured without minding their gestational background.

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., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Objective: Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655)., Methods: Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1-4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics., Results: Vandetanib + metformin increased metformin area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and maximum observed plasma concentration (Cmax) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0-last) and Cmax by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated., Conclusion: Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug-drug interactions.

To characterize and compare acid suppression (pharmacodynamics) and pharmacokinetics of IV famotidine and ranitidine in critically ill children at risk for stress gastritis. Single-blind, randomized study in PICU patients 6 months to 18 years requiring mechanical ventilation with continuous gastric pH monitoring, randomized to IV famotidine 12 mg/m(2) or ranitidine 60 mg/m(2) when gastric pH < 4.0 >1 hour with serial blood sampling following first dose. Twenty-four children randomized to either famotidine (n = 12) or ranitidine (n = 12). Sixteen out of twenty-four completed both PK and PD study arms (7/12 famotidine; 4.7 ± 3.4 years; 9/12 ranitidine; 6.6 ± 4.7 years; p = 0.38). Time to gastric pH 4.0 and total time pH above 4.0 similar with no difference in pH at 6 and 12 hours (p > 0.2). No difference between drugs in clearance, volume of distribution and half-life (p > 0.05). Ratio of AUC pH to AUC drug concentration 0-12 hours after first dose was significantly greater for famotidine (0.06849 ± 0.01460 SD) than ranitidine (0.02453 ± 0.01448; p < 0.001) demonstrating greater potency of famotidine. pH lowering efficacy of both drugs is similar. Greater potency of famotidine may offer clinical advantage due to lower drug exposure and less frequent dosing to achieve same pH lowering effect., (© 2013, The American College of Clinical Pharmacology.)

Aims of the Study: This study was to investigate the gastrokinetic activity of Morinda citrifolia aqueous fruit extract (AFE) in human subjects by examining the GI absorption of ranitidine, a putative indicator of GI motility and to elucidate its possible gastrokinetic mechanism of action in rats., Materials and Methods: The single-dose, randomized, open-label and 2-period crossover study was performed on 20 Thai healthy volunteers with a washout period of 14 day between the doses. AFE or drinking water was administered orally 30 min prior to a single oral administration of ranitidine (300 mg). Blood samples were collected over a 12 h period after drug administration and the pharmacokinetic parameters of ranitidine were calculated. The gastrokinetic mechanism of action of AFE was elucidated by measurement of its contractile response on the isolated rat gastric fundus strip., Results: The area under the plasma ranitidine concentration-time curve and the maximal plasma ranitidine concentration were significantly increased after pretreatment with AFE (p=0.001). The plasma ranitidine concentrations were significantly greater at 30-120 min after its administration. AFE produced a definite contractile response of a rat gastric fundus strip with a dose dependency. Scopoletin at the same equivalent dose present in AFE elicited a concentration-dependent contraction that amounted to 45% of the maximal response to AFE. The contractile response of both AFE and scopoletin was mediated through the 5-HT(4) receptor., Conclusion: AFE has a unique gastrokinetic activity in enhancement of the rate and the extent of ranitidine absorption. The underlying mechanism can be attributed, at least in part, to the ability of its active component: scopoletin to stimulate the 5-HT(4) receptor., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

A novel precolumn derivatization reversed-phase high-performance liquid chromatography method with fluorescence detection is described for the determination of ranitidine in human plasma. The method was based on the reaction of ranitidine with 4-fluoro-7-nitrobenzo-2-oxa-1,3-diazole forming yellow colored fluorescent product. The separation was achieved on a C(18) column using methanol-water (60:40, v/v) mobile phase. Fluorescence detection was used at the excitation and emission of 458 and 521 nm, respectively. Lisinopril was utilized as an internal standard. The flow rate was 1.2 mL/min. Ranitidine and lisinopril appeared at 3.24 and 2.25 min, respectively. The method was validated for system suitability, precision, accuracy, linearity, limit of detection, limit of quantification, recovery and robustness. Intra- and inter-day precisions of the assays were in the range of 0.01-0.44%. The assay was linear over the concentration range of 50-2000 ng/mL. The mean recovery was determined to be 96.40 ± 0.02%. This method was successfully applied to a pharmacokinetic study after oral administration of a dose (150 mg) of ranitidine., (© The Author [2012]. Published by Oxford University Press. All rights reserved.)

As 95% of all prescriptions are for orally administered drugs, the issue of oral absorption is central to the development of pharmaceuticals. Oral absorption is limited by a high molecular weight (>500 Da), a high log P value (>2.0) and low gastrointestinal permeability. We have designed a triple action nanomedicine from a chitosan amphiphile: quaternary ammonium palmitoyl glycol chitosan (GCPQ), which significantly enhances the oral absorption of hydrophobic drugs (e.g., griseofulvin and cyclosporin A) and, to a lesser extent, the absorption of hydrophilic drugs (e.g., ranitidine). The griseofulvin and cyclosporin A C(max) was increased 6- and 5-fold respectively with this new nanomedicine. Hydrophobic drug absorption is facilitated by the nanomedicine: (a) increasing the dissolution rate of hydrophobic molecules, (b) adhering to and penetrating the mucus layer and thus enabling intimate contact between the drug and the gastrointestinal epithelium absorptive cells, and (c) enhancing the transcellular transport of hydrophobic compounds. Although the C(max) of ranitidine was enhanced by 80% with the nanomedicine, there was no appreciable opening of tight junctions by the polymer particles.

A novel approach has been developed to determine ranitidine in paediatric samples using dried blood spots (DBS) on Guthrie cards (Whatman 903). A selective and sensitive HPLC-MS/MS assay has been developed and validated using small volumes of blood (30 μl). A 6 mm disc was punched from each DBS and extracted with methanolic solution of the internal standard (IS) nizatidine. This was further subjected to solid phase extraction (SPE), followed by reversed phase HPLC separation, using a XBridge™ C18 column and mobile phase 10 mM ammonium acetate/methanol (98:2 v/v) with a flow rate of 0.3 mL/min. This was combined with multiple reaction monitoring (MRM) mass detection using electrospray ionisation (ESI). The calibration curve for ranitidine was found linear over the range 10-500 ng/mL (r=0.996). The limit of quantification (LOQ) of the method was validated at 10 ng/mL. Accuracy and precision values for within and between days were <20% at the LOQ and <15% at all other concentrations. The validated DBS method was successfully applied to a clinical study employing 81 samples from 36 paediatric patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A new, simple, and reliable reversed-phase high-performance liquid chromatographic method has been developed and validated for the simultaneous determination of metformin (Metf), cimetidine (Cimt), famotidine (Famt), and ranitidine (Rant) in their synthetic mixtures and tablet formulations. These drugs were separated on a Purospher Star RP18 endcapped (250 mm × 4.6 mm i.d.) column packed with 5-μm particles. The mobile phase, optimized through an experimental design, consisted of methanol-water-triethylamine (20:80:0.05), whose pH was adjusted to 3.0 with phosphoric acid (85%) pumped at a flow rate of 1.0 mL/min. UV detection was performed at 229 nm. The method was validated in the sample concentration range of 5-25 μg/mL for all the drugs, where it demonstrated good linearity with r = 0.9998, 0.9979, 0.9997, and 0.9987 (n = 6), respectively. For independent 100% level samples, the intra-day and inter-day precision was in the range i.e. < 2.0 for all the drugs. The method demonstrated robustness, resisting to small deliberate changes in pH, flow rate, and composition (organic:aqueous ratio) of the mobile phase. The limit of detection values were 0.071, 0.116, 0.134, and 0.110 μg/mL, while the limit of quantitation were 0.217, 0.352, 0.405, and 0.368 μg/mL for Metf, Cimt, Famt, and Rant, respectively. The applicability of the method was demonstrated by determining the drug content in pharmaceutical formulations, where it exhibited good performance.

A simple, specific and accurate reverse phase liquid chromatographic method has been developed for the simultaneous determination of naproxen and ranitidine HCl. Both the drugs are official with British Pharmacopoeia 2007, but do not involve simultaneous determination of naproxen and ranitidine HCl. The separation was carried out using 4.6 × 250 mm Symmetry Shield TM RP 18 with a particle diameter of 5 µm and mobile phase containing 0.1M orthophosphoric acid: methanol (35:65, pH 3.1) in isocratic mode. The flow rate was 1.00 ml/min and effluent was monitored at 240 nm. The retention times (average) of ranitidine HCl and naproxen were 2.36 min and 12.39 min, respectively. The linearity for naproxen and ranitidine HCl was in the range of 5-35 µg/ml and 1.5-12 µg/ml, respectively. The potencies of naproxen and ranitidine HCl were found 99.40 % and 99.48 %, respectively. The proposed method was validated and successfully applied to the estimation of naproxen and ranitidine HCl in newly formulated combined tablet and in plasma.

A sensitive and universal LC-MS/MS method for the simultaneous determination of famotidine, cimetidine, ranitidine and lafutidine in human plasma was presented. This is the first single LC-MS/MS method reported for the simultaneous analysis of these four H(2) antagonists in human plasma. Following liquid-liquid extraction with ethyl acetate, the separation was performed on an Agilent Zorbax SB-CN (150 mm x 2.1mm I.D., 5 microm) column using a mobile phase consisted of methanol:20 mM ammonium acetate (55:45, v/v). The total run time was 7 min per sample. Quantification was performed by electrospray ionization-triple quadrupole mass spectrometry by selected reaction monitoring (SRM) detection in the positive mode. All calibration curves showed good linear regression (r(2)>0.99) from 0.5 to 1000 ng/mL for famotidine and lafutidine, and 5-20,000 ng/mL for cimetidine and ranitidine. The method showed good precision and accuracy with overall intra- and inter-day variations of 1.37-9.29% and 3.51-9.40%, respectively. The assay was successfully applied to a bioequivalence study using ranitidine as the model compound.

Background: Acetaminophen, caffeine, phenytoin, ranitidine, and theophylline are widely used in pediatric pharmacotherapy, but only very limited information is available on the pharmacokinetics of these medications in premature neonates. As pharmacokinetic studies in this population are hampered by limitations in the number and volume of plasma samples, we developed an LC-MS/MS assay for the simultaneous determination of these medications in small volume human plasma specimens for pharmacokinetic evaluations in neonates., Methods: Sample preparation was performed by protein precipitation with methanol after addition of internal standard to 50 microl of plasma specimen. After chromatographic separation on a C18 column using gradient elution, analytes were detected using a triple quadrupole mass spectrometer that was operated in positive ion mode with electrospray ionization., Results: All 5 analytes could be simultaneously quantified in human plasma. The linear quantification range comprised 12.2 to 25,000 ng/ml for acetaminophen, phenytoin, and ranitidine, 24.4 to 25,000 ng/ml for theophylline, and 48.8 to 25,000 ng/ml for caffeine with accuracies ranging from 87.5 to 115.0%. The intra-day and inter-day precision (%CV) was between 2.8 and 11.8% and 4.5 and 13.5%, respectively., Conclusions: An accurate, sensitive, and reliable LC-MS/MS method was developed and validated to simultaneously quantify 5 drugs frequently used in neonatal pharmacotherapy.

The present research is based on the hypothesis that leaky enteric-coated pellets formulations are able to provide sustained input for drugs that have an absorption window, such as ranitidine hydrochloride, without jeopardizing their bioavailability. Leaky enteric-coated pellets formulations are defined as enteric-coated pellets that allow some of the drug to be released from the formulation in gastric fluid. Different approaches to making leaky enteric-coated pellets were investigated using extrusion-spheronization followed by spray coating. Leaky enteric coats were formulated using a commonly used enteric polymer, Eudragit L 30 D-55, combined with soluble compounds including lactose, PEG 8000 and surfactants (Span 60 (hydrophobic) or Tween 80 (hydrophilic)). The rate of drug release from the formulations in simulated gastric fluid can be tailored by varying the additive's amount or type. All leaky enteric-coated formulations studied completely released the drugs within 30 min after changing dissolution medium to phosphate buffer, pH 6. Predictions of plasma concentration-time profiles of the model drug ranitidine hydrochloride from leaky enteric-coated pellets in fasted conditions and from immediate-release formulations were performed using computer simulations. Simulation results are consistent with a hypothesis that leaky enteric-coated pellets formulations provide sustained input for drugs shown to have an absorption window without decreasing bioavailability. The sustained input results from the combined effects of the formulation and GI transit effects on pellets. The present research demonstrates a new application of knowledge about gastrointestinal transit effects on drug formulations. It also shows that enteric-coating polymers have new applications in areas other than the usual enteric-coated formulations. The hypothesis that a leaky enteric-coated pellets formulation may maintain or increase the bioavailability of drugs that have a window of absorption is still to be confirmed by further in vivo studies.

Da Cheng Qi decoction (DCQD) is composed of Dahuang, Houpu, Zhishi and Mangxiao. It is a formula created under the theory of Chinese medicine to purge the 'evil heat' in the gastrointestitinal tract, which arises from the ileus and acute pancreatitis. The present study was conducted to evaluate the herb-drug interaction between DCQD and ranitidine, which are often co-administered in clinical practice. Ranitidine was administered orally alone or together with DCQD to rats, and plasma ranitidine concentrations were measured by HPLC. Following oral administration, ranitidine plasma levels revealed curves characterized by peaks at 1.8 and 4.2 h corresponding to ranitidine alone and ranitidine with DCQD at mean concentrations of 16.315 and 1.455 microg/mL, respectively. After ranitidine was orally dosed alone or with DCQD, the half-lives were 1.787 and 3.758 h, while the area under the concentration-time curve (0-12 h) was 28.083 and 9.826 microg/L h, respectively, suggesting that DCQD might significantly affect the pharmacokinetics of ranitidine in rats. When physicians or pharmacists administer DCQD and ranitidine, they must make a careful effort to adjust the dosage of the drug and Chinese decoction, or avoid the herb-drug co-administration., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

A sensitive high-performance liquid chromatographic method for determination of ranitidine (RAN) in rabbit plasma is described. The method is based on liquid-liquid extraction, labeling with dansyl chloride and monitoring with fluorescence detector at 338nm (ex)/523nm (em). Plasma samples were extracted with diethyl ether alkalinized with 1M sodium hydroxide. Ephedrine HCl (EPH-HCl) was used as internal standard. Both, RAN and EPH were completely derivatized after heating at 60 degrees C for 10min in sodium bicarbonate solution (pH 9.5). The derivatized samples were analyzed by HPLC using Agilent Zorbax Extended C18 column (150mmx4.6mm i.d.) and mobile phase consists of 48% acetonitrile and 52% sodium acetate solution (0.02M, pH 4.6). The linearity of the method was in the range of 0.025-10microg/ml. The limits of detection (LOD) and quantification (LOQ) were 7.5+/-0.18 and 22.5+/-0.12ng/ml, respectively. Ranitidine recovery was 97.5+/-1.1% (n=6; R.S.D.=1.8%). The method was applied on plasma collected from rabbits at different time intervals after oral administration of 5mg/kg ranitidine HCl.

The effect of silymarin pretreatment on the pharmacokinetics of ranitidine was investigated in 12 healthy male human volunteers aged 19-26 years. After an overnight fast, ranitidine 150 mg was administered to the volunteers either alone or after 7 days pretreatment with thrice daily dose of 140 mg silymarin. The wash-out period between each treatment was 7 days. Serum levels of ranitidine were determined by HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program KINETICA. There was no influence of silymarin on the pharmacokinetics of ranitidine. Concomitant administration of silymarin at this dosage did not alter ranitidine C(max) and AUC(0-infinity). There was a significant difference in area under the first moment curve (AUMC) and mean residence time. This result is useful in predicting the interaction of silymarin with other cytochrome 3A4 and P-glycoprotein substrates at normal dosage.

Aim: To evaluate the bioequivalence of ranitidine and bismuth derived from two compound preparations., Methods: The bioavailability was measured in 20 healthy male Chinese volunteers following a single oral dose (equivalent to 200 mg of ranitidine and 220 mg of bismuth) of the test or reference products in the fasting state. Then blood samples were collected for 24 h. Plasma concentrations of ranitidine and bismuth were analyzed by high-performance liquid chromatography and inductively coupled plasma-mass spectrometry (ICP-MS), respectively. The non-compartmental method was used for pharmacokinetic analysis. Log-transformed C(max), AUC( (0-t) ) and AUC( (0-infinity) ) were tested for bioequivalence using ANOVA and Schuirmann two-one sided t-test. T(max) was analyzed by Wilcoxon's test., Results: Various pharmacokinetic parameters of ranitidine derived from the two compound preparations, including C(max), AUC( (0-t)), AUC( (0-infinity)), T(max) and T((1/2)), were nearly consistent with previous observations. These parameters derived from test and reference drug were as follows: C(max) (0.67 +/- 0.21 vs 0.68 +/-0.22 mg/L), AUC( (0-t) ) (3.1 +/- 0.6 vs 3.0 +/- 0.7 mg/L per hour), AUC( (0-infinity) ) (3.3 +/- 0.6 vs 3.2 +/- 0.8 mg/L per hour), T(max) (2.3 +/- 0.9 vs 2.1 +/- 0.9 h) and T((1/2)) (2.8 +/- 0.3 vs 3.1 +/- 0.4 h). In addition, double-peak absorption profiles of ranitidine were found in some Chinese volunteers. For bismuth, those parameters derived from test and reference drug were as follows: C(max) (11.80 +/- 7.36 vs 11.40 +/- 6.55 microg/L), AUC( (0-t) ) (46.65 +/- 16.97 vs 47.03 +/- 21.49 microg/L per hour), T(max) (0.50 +/- 0.20 vs 0.50 +/- 0.20 h) and T((1/2)) (10.2 +/- 2.3 vs 13.0 +/- 6.9 h). Ninety percent of confidence intervals for the test/reference ratio of C(max), AUC( (0-t) ) and AUC( (0-infinity) ) derived from both ranitidine and bismuth were found within the bioequivalence acceptable range of 80%-125%. No significant difference was found in T(max) derived from both ranitidine and bismuth., Conclusion: The two compound preparations are bioequivalent and may be prescribed interchangeably.

A high-performance liquid chromatography method using ultraviolet detection at 230 nm for the simultaneous determination of amoxicillin and ranitidine in rat plasma has been validated. Plasma samples after pretreatment with acetonitrile to effect deproteinization were dried under N2 and reconstituted with water. The standard calibration curves for amoxicillin and ranitidine were linear (r2=0.9999) over the concentration range of 0.2-20 microg ml-1 and 0.03-6 microg ml-1 in rat plasma, respectively. The intra- and inter-day assay variability range for amoxicillin was 2.4-8.5% and 3.2-11.7%, and for ranitidine was 1.7-9.0% and 4.5-10.1%, respectively. This method has been successfully applied to a pharmacokinetic study after oral coadministration of amoxicillin and ranitidine to rats.

To investigate the pharmacokinetics of unbound ranitidine in rat blood and bile, multiple microdialysis probes coupled to a liquid chromatographic system were developed. This study design was parallel in the following groups: the control-group of six rats received ranitidine alone (10 and 30 mg/kg, i.v.), the treated-group rats were co-administered with ranitidine and cyclosporine (P-glycoprotein (P-gp) inhibitor) or quinidine (both organic cation transport (OCT) and P-gp inhibitors) in six individual rats. Microdialysis probes were inserted into the jugular vein and the bile duct for blood and bile fluids sampling, respectively. Ranitidine in the dialysate was separated by a reversed-phase C18 column (Zorbax, 150 mm x 4.6 mm i.d.; 5 microm) maintained at ambient temperature. Samples were eluted with a mobile phase containing acetonitrile-methanol-tetrahydrofuran-20 mM K2HPO4 (pH 7.0) (24:20:10:946, v/v), and the flow rate of the mobile phase was 1 ml/min. The optimal UV detection for ranitidine was set at wavelength 315 nm. Between 20 and 30 min after drug administration (10 or 30mg/kg), the ranitidine reached the maximum concentration in the bile. The bile-to-blood distribution ratio (AUC(bile)/AUC(blood)) was 9.8 +/- 1.9 and 13.9 +/- 3.8 at the dosages of 10 and 30 mg/kg, respectively. These studies indicate that ranitidine undergoes hepatobiliary excretion which against concentration gradient from bile-to-blood. In addition, the AUC of ranitidine in bile decreased in the treatment of cyclosporine or quinidine, which suggests that the hepatobiliary excretion of ranitidine was partially regulated by P-glycoprotein or organic cation transporter.

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.

The development and validation of a simple method for the simultaneous determination of ranitidine and metronidazole in human plasma is described. Plasma samples (250 microL) were deproteinized by precipitation with 60% perchloric acid, centrifuged and the supernatant directly injected into the HPLC. Separation was achieved in isocratic mode with a Shimpak C(18) column and a mobile phase consisting of 10mM potassium dihydrogen phosphate pH 3.5:acetonitrile (90:10, v/v) with UV detection at 315 nm. The method showed good selectivity and sensitivity. Good and consistent recovery for metronidazole and ranitidine was obtained: 96.22+/-3.52 and 95.00+/-4.50% for ranitidine (25-1000 ng/mL) and metronidazole (60-10,000 ng/mL), respectively (n=3). With this one-step sample preparation method, both ranitidine and metronidazole could be quantified simultaneously in human plasma with good precision (R.S.D.<15%) and accuracy (bias values below 15%). The limit of quantification for ranitidine and metronidazole were 20 and 40 ng/mL plasma, respectively.

HPLC methodology was investigated for the simultaneous determination of cisapride and ranitidine in small volume paediatric plasma samples. Such a simultaneous determination proved difficult due to the small sample volumes, the low concentrations of the drugs and the different log P values of the two compounds. The two drugs and their respective internal standards were separated "on-cartridge" using HLB Solid Phase Extraction cartridges and the samples quantified by individual HPLC methodologies. The technique has been applied successfully to 60 paediatric plasma samples containing both cisapride and ranitidine.

The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract.

A validated HPLC method for the determination of ranitidine in human plasma is presented. Sulfanilamide as internal standard (IS) was used. Plasma samples were purified by solid phase extraction (SPE) using a copolymeric [poly(divinyl-benzene-co-N-vinylpyrrolidone)] column ("Oasis Waters"). Mobile phase consisting of dibasic potasium phosphate 0.08 M/acetonitrile/methanol/triethylamine 0.05% (89.5:3:7:0.05) pH5 was used at a flow rate of 0.9 ml/min on a C18 column (Nova-Pack, 3,9 x 300 mm, Waters). The eluate was monitored using an UVNis detector set at 300 nm. Ratio of peak area of ranitidine to sulfanilamide was used for the quantitation of plasma samples. FDA criteria for bioanalytical validation was used to validate the method. Linearity was assessed between 100-1600 ng/ml, the limit of quantitation was 100 ng/ml and recovery was greater than 94%. Accuracy, precision and selectivity met the current recommendations for bioanalytical method validation. The method was successfully used in a bioavailability study of a ranitidine tablet in healthy volunteers.

The aim of the present study was to develop a simple method to measure ranitidine, using 100 microL of plasma, by high-performance liquid chromatography with a Symmetry C(18) column and UV detection at 313 nm. Linearity was assessed in the range from 50 to 1500 ng ml(-1) and had a correlation coefficient of 0.999. The inter- and intra-day coefficients of variation were less than 7%. The limits of detection and quantitation were 5 and 15 ng ml(-1), respectively. Drug levels were determined satisfactorily in three patients. A simple and reliable method was developed which uses a microvolume of plasma, particularly useful in low-weight children.

A selective, sensitive and accurate high-performance liquid chromatographic method has been developed, validated and applied for the determination of ranitidine and cimetidine in plasma samples. The effects of mobile phase composition, buffer concentration, mobile phase pH and concentration of organic modifiers on retention of investigated drugs were investigated. Sample preparation was carried out by adding an internal standard, famotidine, and the clean-up procedure was accomplished using solid-phase extraction (SPE). This method uses ultraviolet detection, the separation used a Lichrocart Lichrospher 60 RP-select B column and the mobile phase consisted of 0.2% triethylamine (TEA), 0.04 mol l(-1) KH2PO4 at pH 6.8 and 14% acetonitrile. The recovery, selectivity, linearity, precision and accuracy of the method were evaluated from spiked human plasma. The method has been implemented to monitor ranitidine levels in clinical samples.

The present study was undertaken to determine if differences exist in the pharmacokinetic parameters of oral ranitidine caused by gender and stage of the menstrual cycle. The study was performed in two steps, in the first a pharmacokinetic study was performed on 10 men (average age 35.5 yrs) and 10 women (average age 34.7 yrs) during the follicular phase, and in the second the pharmacokinetic study was performed only on the same women in their luteal phase. Subjects received a tablet dose of 300 mg ranitidine, and blood samples were drawn at several times after its ingestion. Plasma ranitidine concentration was determined by high performance liquid chromatography. Comparison of the pharmacokinetic parameters of women and men revealed statistically significant differences both in distribution volume (Vd) with values of 2.0 and 6.3 l/kg, Area Under Curve (AUC) with values of 7312.15 and 11471.94 ng/ml/h, and clearance (CLt) with values of 0.65 and 0.59 l/kg/h, respectively. Several pharmacokinetic parameters in women were different in the follicular compared to the luteal phase; for example, Vd was 2.0 and 5.6 l/kg, AUC was 7312.15 and 5195.83 ng/ml/h, and CLt was 0.65 and 0.97 l/kg/h, in the respective phases. Moreover, the maximum concentration (Cmax) was 1086 ng/ml in the follicular vs. 864 ng/ml in the luteal phase. The first study detected differences between men and women in several pharmacokinetic parameters, mainly those indicative of drug availability, for example, Vd, AUC, and CLt. Comparison of data obtained in the follicular phase with those obtained in the luteal phase revealed differences in most pharmacokinetic parameters, which is seemingly indicative of the characteristic physiological changes associated with the luteal phase that largely affect the kinetics and availability of drugs such as ranitidine. Although it has been postulated that hormonal fluctuation within the menstrual cycle phase is the primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs, further study of related factors is required to understand how gender and menstrual cycle rhythms affect the phannacokinetic process in their entirety.

A simple and sensitive capillary electrophoresis method using UV detection has been developed for the direct determination of ranitidine (RANT) and famotidine (FAMT) in serum, urine and pharmaceutical formulations. A buffer consisting of 60 mM phosphate buffer adjusted to pH 6.5 was found to provide a very efficient and stable electrophoretic system for the analysis of both drugs. The detection limits obtained were 0.088 microgram ml(-1) for RANT and 0.16 microgram ml(-1) for FAMT.

Purpose: To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract., Methods: Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-III to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration., Results: The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and Cmax parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400., Conclusions: These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.

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.

Is well known that food can affect the bioavailability of several drugs, its impact is major for those drugs that have to act near of drug absorption. Documentation about alterations of ranitidine bioavailability by effect of food is poor. The purpose of this work was to evaluate the effect of food over the bioavailability of ranitidine. Twenty healthy Mexican volunteers were included for the study. The study was made in two stages, in the first one the volunteers had 12 hour fast and took a 300 mg of oral dose of ranitidine (without food, WOF) and blood samples were drawn. Two weeks later, the volunteers took a normal diet just before ranitidine intake (with food, WF). The area under the curve (AUC) was 30% greater in WOF, Cmax was 921.5 ng/ml (WF) vs. 1685.2 (WOF), and t1/2 was 2.70 +/- 1.38 (WF) h vs 3.66 +/- 1.34 (WOF). The AUC, Cmax and t1/2 were statistically different. It is evident that there are differences in the drug disposition due to the presence of food, then, it is possible that the efficacy of ranitidine as inhibitor of gastric secretion being limited by food.

A sensitive HPLC method for the determination of ranitidine in small-volume (0.5 mL) paediatric plasma samples is described. Plasma samples were extracted using a simple, rapid solid phase extraction (SPE) technique developed using disposable copolymer packed SPE cartridges. Chromatographic separation was achieved by reverse-phase HPLC with isocratic elution using a microBondapak C18 column and a phosphate buffer (10 mM, pH 3.75)-acetonitrile (87:13 v/v) mobile phase with UV detection at 313 nm. The HPLC system exhibited linearity in the range 8-800 ng mL(-1). Intraday % CV and % bias values were in the range 1.28-8.09% (% bias -4.33 to -0.87) and interday % CV and % bias values were in the range 0.73-15.28% (% bias -1.80 to + 1.65). The limits of detection and quantitation obtained were 2 ng mL(-1) and 8 ng mL(-1), respectively, and ranitidine extraction recoveries from plasma ranged from 92.30 to 103.88%. In this study, the developed HPLC and SPE methodologies have been successfully applied to the determination of ranitidine concentrations in 68 paediatric plasma samples. The sampled population was drawn from patients already receiving the study drug therapeutically. Patients recruited had received ranitidine by two main routes - oral and intravenous. The plasma concentrations of ranitidine encountered in paediatric samples following oral or intravenous administration of a range of prescribed doses are presented graphically. These profiles are based on analysis of the first 68 plasma samples obtained from the first 35 patients recruited to the study receiving ranitidine by the oral or intravenous route.

In this study, low concentrations of histamine2-receptor (H2-)antagonists were effected across a water plug, with separation taking place in a binary buffer comprising ethylene glycol and NaH2PO4 (pH 5.0), and detection at 214 nm. Liquid-liquid extraction with ethyl acetate- isopropanol is shown to provide extracts that are sufficiently clean. The calibration curves were linear over a concentration range of 0.1-2.00 microg/mL cimetidine, 0.2-5.0 microg/mL ranitidine-HCl, 0.3-5.0 microg/mL nizatidine, and 0.1-3.0 microg/mL famotidine. Mean recoveries were > 82%, while the intra- and interday relative standard deviations (RSDs) and relative errors (REs) were all < 13%. The method is sensitive with a detection limit of 3 ng/mL cimetidine, 30 ng/mL ranitidine HCl, 50 ng/mL nizatidine and 10 ng/mL famotidine (S/N = 3, electric-driven injection 90 s). This newly developed capillary electrophoresis (CE) method was applied for the determination of analytes extracted from plasma taken from a volunteer dosing a cimetidine, ranitidine, and nizatidine tablet simultaneously. These three H2-antagonists can be detected in real samples by this method, excluding the low dosing of famotidine tablet.

Objective: To determine the pharmacokinetics and pharmacodynamics of ranitidine in critically ill children and to design a dosage regimen that achieves a gastric pH > or =4., Design: Prospective, open-label, pharmacokinetic-pharmacodynamic study., Setting: Pediatric intensive care unit in a tertiary care children's hospital., Patients: Mechanically ventilated, critically ill children > or =10 kg who required intravenous ranitidine for stress ulcer prophylaxis., Interventions: Ranitidine pharmacokinetics were determined after a single intravenous dose. Gastric pH was monitored hourly via nasogastric pH probe. After the last blood sample, patients received an intravenous bolus of ranitidine (0.5 mg/kg) followed by a continuous infusion (0.1 mg x kg(-1) x hr(-1)). The infusion was increased incrementally (0.05 mg x kg(-1) x hr(-1)) until reaching gastric pH > or =4 for > or =75% of a 24-hr period, after which steady-state plasma concentrations were measured. Plasma concentrations were analyzed by high-pressure liquid chromatography., Measurements and Main Results: Twenty-three children (ranging in age from 1.4 to 17.1 yrs) were studied. Pharmacokinetic variables included a clearance of 511.7 +/- 219.7 mL x kg(-1) x hr(-1), volume of distribution of 1.53 +/- 0.99 L/kg, and half-life of 3.01 +/- 1.35 hrs. After the single intravenous dose (1.52 +/- 0.47 mg/kg), gastric pH increased from 1.6 +/- 1.0 to 5.1 +/- 1.1 (p <.001), which was associated with a plasma concentration of 373 +/- 257 ng/mL. Based on the pharmacokinetic variables, the dose of intravenous ranitidine required to target 373 ng/mL as the average steady-state concentration is 1.5 mg/kg administered every 8 hrs. During the continuous infusion, the mean steady-state ranitidine concentration associated with gastric pH > or =4 was 287 +/- 133 ng/mL. This concentration may be achieved with an intravenous loading dose of 0.45 mg/kg followed by a continuous infusion of 0.15 mg x kg(-1) x hr(-1)., Conclusions: The pharmacokinetics of ranitidine in critically ill children are variable. The description of ranitidine's pharmacokinetics and pharmacodynamics in this study may used to design an initial ranitidine dosage regimen that targets a gastric pH > or =4. Thereafter, gastric pH should be monitored and the dose of ranitidine adjusted accordingly.

A simple high-performance liquid chromatographic procedure was developed for the determination of ranitidine in human plasma. The method entailed direct injection of the plasma samples after deproteination using perchloric acid. The chromatographic separation was accomplished with an isocratic elution using mobile phase consisting of 21 mM disodium hydrogen phosphate-triethylamine-acetonitrile (1000:60:150, v/v), pH 3.5. Analyses were run at a flow-rate of 1.3 ml/min using a microbondapak C18 column and ultraviolet detection at a wavelength of 320 nm. The method was specific and sensitive, with a quantification limit of approximately 20 ng/ml and a detection limit of 5 ng/ml at a signal-to-noise ratio of 3:1. The mean absolute recovery was about 96%, while the within- and between-day coefficient of variation and percent error values of the assay method were all less than 8%. The linearity was assessed in the range of 20-1000 ng/ml plasma, with a correlation coefficient of greater than 0.999. This method has been used to analyze several hundred human plasma samples for bioavailability studies.

Objective: To compare the effect of hemodialysis using two different types of dialyzer membranes, polysulfone (PS), a high-flux membrane, and cuprophane (CP), a conventional membrane, on blood ranitidine concentration., Background: Recent advances in hemodialyzer membranes have improved the removal of small and middle size uremic toxins, while little is known about the change of drug removal by new membranes., Methods: Eight patients with chronic renal failure who received ranitidine (150 mg/day) on a chronic basis were included. During the dialysis, blood samples were obtained from both the arterial and venous sides (before and after, respectively) of the dialyzer., Results: Serum concentration of ranitidine decreased more on PS [54 +/- 3% (+/- SEM) reduction after 3 h] than on CP (35 +/- 4%). The dialyzer clearance of ranitidine on PS membrane (67.2 +/- 4.4 ml/min/m2) was significantly higher than that on CP (43.1 +/- 3.8 ml/min/m2, P < 0.001). Elimination fraction (EF) of the drug during the dialysis with PS was also significantly higher than that with CP (72 +/- 2% versus 44 +/- 3%). Apparent half-life of ranitidine during dialysis with PS (2.9 +/- 0.4 h) was shorter than that with CP (5.1 +/- 0.7 h). However, the amount of ranitidine removed by a single dialysis with PS membrane was less than 20 mg., Conclusion: Ranitidine clearance by hemodialysis is significantly higher with PS than with CP. Although additional dose adjustment may not be needed for ranitidine, the type of dialyzer membrane can affect drug elimination and should be taken into account for consideration of drug removal by hemodialysis.

To investigate the effect of two prokinetic drugs, cisapride and metoclopramide, on the bioavailability of drugs, a marker drug, ranitidine, was administered to healthy volunteers following pre-treatments with or without the prokinetic agents. Cisapride or metoclopramide HCl (a respective dose of 10 mg) was administered orally 30 min prior to an oral administration of ranitidine (300 mg). Serum samples were collected for a 12 h period after the administration of ranitidine and the concentration of ranitidine was determined by an HPLC method. The bioavailability parameters of the groups with the prokinetic agent pretreatment were compared with those of the control group. In addition, the effects of these prokinetic drugs on the in vitro apparent permeability of ranitidine across the rat jejunum in the Ussing chamber, and on the in vivo intestinal transit of charcoal meals in rats were also examined. The Tmax of ranitidine in human subjects was shortened significantly by the either of the pretreatments (i.e., with cisapride and metoclopramide). The AUC(inf) of ranitidine in human subjects was also decreased significantly in the case of cisapride pretreatment. However, no changes were observed for the values of Cmax and T(1/2) by the pretreatments. Rat studies revealed that cisapride and metoclopramide had no influence on the in vitro permeability of ranitidine or the in vivo intestinal transit of charcoal meals. Therefore, these data indicated that the changes in the bioavailability parameters (i.e., Tmax and AUC(inf)) in humans are not related with the intestinal permeability or intestinal transit of ranitidine. The shortened Tmax of ranitidine appears to be due to accelerated gastric emptying of the drug. However, underlying mechanisms for the decreased AUC(inf) of ranitidine in the case of cisapride pretreatment are currently unclear.

The pharmacokinetics of oral ranitidine were studied in 9 patients (ages 9.9 to 19.6 years) with cystic fibrosis (CF). Patients were evaluated at steady-state conditions, and the mean maximum serum concentration (Cmax) was 845.7 +/- 448.1 ng/mL. To adjust for the variable drug dosing used among study patients, both Cmax and area under the concentration curve (AUC) were standardized to dose (CmaxST and AUCST, respectively) and were 217.9 +/- 87.9 ng/mL and 1038.0 +/- 242.2 ng/mL.h. The elimination half-life (t1/2) was 2.7 +/- 1.4 hours, and the apparent steady-state volume of distribution (Vdss) was 4.6 +/- 1.7 L/kg. The plasma clearance was 1.022 +/- 0.290 L/kg/h. The Vdss in this study was greater than that previously reported in children with peptic ulcer disease. Statistically significant relationships between pharmacokinetic parameters and measures of disease severity were not observed in the study population. The pharmacokinetics of ranitidine in children and adolescents with CF may differ from those in children and adolescents without CF.

Objective: To characterize the relationship between the pharmacokinetics and the acid inhibitory effect of ranitidine during prolonged dosing on the basis of a physiologic indirect-response model., Methods: Multiple doses of ranitidine were administered to 18 patients in an intensive care unit in an open randomized trial. All patients received an initial intravenous dose of 50 mg ranitidine; after 12 hours repeated injections (50 mg every 6 hours) or a primed continuous infusion (50 mg plus 0.125 mg/kg/h) was administered. Intragastric pH was monitored continuously for at least 42 hours., Results: After the initial injection a time lag was observed between the increase of plasma concentration and the increase of pH. With the indirect-response model the rate of onset of effect (kout) could be estimated adequately by relating the inhibitory effect on acid secretion to the concentration according to a sigmoid Emax model. For administration of a single dose, estimated pharmacodynamic parameters were 4.5 +/- 0.9 h(-1) for kout, 1.4 +/- 0.1 for baseline pH, 0.051 +/- 0.012 mg/L for 50% inhibition constant, and 7.0 +/- 1.5 for Hill factor (mean +/- SEM; n = 18). Tolerance developed during subsequent dosing that could be described as a linear increase (beta) of 50% inhibition constant with time (beta = 0.0030 and 0.0045 mg/L/h for repeated and continuous administration, respectively)., Conclusions: The developed physiologic indirect-response model may be used to quantify the pharmacokinetic-pharmacodynamic relationship of ranitidine during single and multiple dosing. During prolonged intravenous dosing, tolerance developed within 42 hours and could be characterized on the basis of the developed indirect-response model.

Background: Patients undergoing biliopancreatic diversion (BPD) may develop gastric ulcers, particularly within the first postoperative year. The prophylactic use of antisecretory compounds at the usual therapeutic doses, mainly conventional H2-receptor antagonists such as ranitidine, may reduce the incidence of this complication, which occurs in approximately 5% of patients after BPD., Methods: The authors measured the plasma concentrations of ranitidine (300 mg orally) in obese patients, before and 8 months after BPD, and in control subjects of normal weight. The study included 11 obese patients undergoing BPD (age 45+/-14 years; preoperative and postoperative weights 124+/-21 and 92+/-11 kg) and 10 normal-weight subjects (age 37+/-13 years, weight 67+/-9 kg)., Results: Postoperative ranitidine plasma concentrations showed only minor differences from preoperative levels, with slightly higher maximum concentrations occurring sooner. The mean area under the curve was on the average 30% higher than preoperatively. All parameters, however, were similar to those in control subjects., Conclusions: BPD per se does not greatly affect the pharmacokinetic behavior of ranitidine, and therefore a conventional dosage regimen appears adequate for the prophylaxis and therapy of gastric ulcers associated with this operation.

A simple high-performance liquid chromatographic method was developed for the determination of ranitidine in human plasma. Prior to analysis, ranitidine and the internal standard (metoprolol) were extracted from alkalinized plasma samples using dichloromethane. The mobile phase was 0.05 M potassium dihydrogenphosphate-acetonitrile (88:12, v/v) adjusted to pH 6.5. Analysis was run at a flow-rate of 1.3 ml/min and at a detection wavelength of 229 nm. The method is sensitive with a detection limit of 1 ng/ml at a signal-to-noise ratio of 3:1, while the quantification limit was set at 15 ng/ml. The calibration curve was linear over a concentration range of 15-2000 ng/ml. Mean recovery value of the extraction procedure was about 90%, while the within-day and between-day coefficients of variation and percent error values of the assay method were all less than 15%.

This investigation was carried out to evaluate the bioavailability of a new tablet formulation of ranitidine HCl (300 mg), Ranid, relative to the reference product, Zantac, (300 mg) tablets. The bioavailability was carried out on 24 healthy male volunteers who received a single dose (300 mg) of the test (T) and the reference (R) products in the fasting state, in a randomized balanced 2-way crossover design. After dosing, serial blood samples were collected for a period of 16 hours. Plasma harvested from blood was analyzed for ranitidine by a sensitive and validated high-performance liquid chromatographic assay. The maximum plasma concentration (Cmax), area under the plasma concentration time curve up to the last measurable concentration (AUC0-t), and to infinity (AUC0-infinity) and the absorption rate (Cmax/AUC0-infinity) were analyzed statistically under the assumption of a multiplicative model. The time to maximum concentration (Tmax) was analyzed assuming an additive model. The parametric confidence intervals (90%) of the mean values of the pharmacokinetic characteristics (AUC0-t, AUC0-infinity), Cmax and Cmax/AUC0-infinity) for T/R ratio were in each case well within the bioequivalence acceptable range of 80-125%. The test formulation was found bioequivalent to the reference formulation by the Schuirmann's two one-sided t-tests and by Wilcoxon Mann Whitney two one-sided tests procedure. Therefore, the 2 formulations were considered to be bioequivalent.

The pharmacokinetics and pharmacodynamics of ranitidine were studied in 13 term neonates with stable renal and hepatic function who were treated with extracorporeal membrane oxygenation (ECMO). Ranitidine was initially administered as a single 2 mg/kg dose over 10 minutes and intragastric pH was monitored to determine response. Within 90 minutes after administration of ranitidine, intragastric pH for all of the patients whose initial reading was < or = 4 had increased to > 5. Intragastric pH remained > 4 for a minimum of 15 hours. Mean +/- 1 standard deviation elimination half-life was 6.61 +/- 2.75 hours, and 41.5 +/- 22.2% of the single dose was eliminated in urine within 24 hours. Total plasma clearance of ranitidine correlated well with estimated glomerular filtration rate. Twenty-four hours after the initial dose, a continuous infusion of ranitidine (2 mg/kg/24 hr) was started and continued for 72 hours or until ECMO was discontinued. Eleven patients completed 48 hours of continuous infusion and seven completed all 72 hours. Plasma clearance and elimination half-life were determined from steady-state plasma ranitidine concentrations 24, 48, and 72 hours after the start of the infusion. There were no significant differences in clearance between these intervals. These data suggest that for term neonates with stable renal and hepatic function, ranitidine does not need to be administered more frequently than every 12 hours. A continuous infusion of 2 mg/kg/24 hours maintained intragastric pH above 4 in more than 90% of our patients, and in our opinion is the preferred method for delivering ranitidine to term neonates undergoing ECMO who require H2 antagonists. Response to therapy should be monitored by repeated measurement of gastric pH and the dose should be adjusted accordingly.