Cimetidine Concentrations Research Articles

Evaluating the radioprotective effect of Cimetidine, IMOD, and hybrid radioprotectors agents: An in-vitro study

IntroductionThere are various radioprotective agents with different mechanisms that help to decrease ionizing radiation side effects. The radioprotective effect of Cimetidine and IMOD was assessed individually and compared with the hybrid radioprotectors agents (HRPAs-IMOD and Cimetidine) on human lymphocyte cells. MethodsTwenty healthy volunteers (ten men and ten women) participated in the present study. About 75 mL peripheral blood lymphocytes from each individual were collected, and they were divided into 36 groups. Briefly, the blood samples were treated with different concentrations of Cimetidine (12.6 and 25.2 μg/mL) and IMOD (0.04, 0.08, and 0.12 mg/mL), and also a combination of these agents, namely hybrid radioprotectors agents (HRPAs). Besides, the irradiated groups were exposed to 2 and 4 Gy of Co-60 gamma irradiation. The amount of cellular damage was assessed using the micronucleus assay. The repeated measurements and paired T-test statistical analysis were used to compare the micronucleus frequencies in different groups. ResultsThe micronucleus frequencies were significantly reduced (p < 0.05) in irradiated groups when the non-toxic concentrations of Cimetidine, IMOD, and HRPAs have been used. The reduction in micronucleus frequency was obtained 5–29% for Cimetidine and 40–51% for IMOD in peripheral blood lymphocytes irradiated with 2 Gy. This reduction in 4 Gy irradiation was 8–17% for Cimetidine and 27–37% for IMOD. The HRPAs resulted in a higher radioprotective effect, in a way that they cause up to 58% and 43% micronucleus frequency reduction in 2 and 4 Gy, respectively. ConclusionIn conclusion, the HRPAs showed the highest level of radioprotective. In addition, IMOD was remarkably higher radioprotective than Cimetidine, which may be related to its greater non-toxic concentrations.

IN VITRO AND IN VIVO EVALUATION OF FLOATING GASTRORETENTIVE DRUG DELIVERY SYSTEM OF CIMETIDINE USING HARD ALGINATE CAPSULES

Objective: The objective of this study was to evaluate in vitro and in vivo of gastroretentive drug delivery system of cimetidine using hard alginate capsules.Methods: Drug release study was tested to various hard alginate capsules containing 200 mg cimetidine with paddle method dissolution apparatus in artificial gastric fluid pH 1.2. Concentrations of cimetidine were measured using ultraviolet spectrophotometer at 218.4 nm wavelength. The product that fulfilled the sustained release profile was evaluated for bioavailability using male rabbits at dose 9.3 mg/kg orally, and the antiulcer studies were evaluated by HCl-induced ulcer method at cimetidine dose 18 mg/kg once a day orally. Gastric lesions were evaluated by macroscopic and microscopic observations.Results: The results of drug release test showed that hard alginate capsule made from sodium alginate 500–600 cP gave sustained release profile of cimetidine for 12 h. In vivo bioavailability studies showed that cimetidine given with hard alginate capsules gave higher of Cmax, Tmax, and area under the curve of cimetidine compared to cimetidine that given with conventional hard gelatin capsules. The antiulcer studies showed that the healing effect of cimetidine that given with hard alginate capsules was faster than cimetidine given in suspension form. Cimetidine that given with hard alginate capsules macroscopically showed no gastric lesion and histopathologically also showed normal gastric mucosa of rats after 4 days treatment. However, cimetidine given in suspension form showed of 0.036±0.024 ulcer index and microscopically there was still erosion of gastric mucosa of rats after 4 days treatment.Conclusion: Floating gastroretentive of cimetidine using hard alginate capsules give a sustained release of cimetidine with better bioavailability and antiulcer effect of cimetidine.

Mechanistic invitro studies confirm that inhibition of the renal apical efflux transporter multidrug and toxin extrusion (MATE) 1, and not altered absorption, underlies the increased metformin exposure observed in clinical interactions with cimetidine, trimethoprim or pyrimethamine.

Metformin is a common co‐medication for many diseases and the victim of clinical drug‐drug interactions (DDIs) perpetrated by cimetidine, trimethoprim and pyrimethamine, resulting in decreased active renal clearance due to inhibition of organic cation transport proteins and increased plasma exposure of metformin. To understand whether area under the plasma concentration–time curve (AUC) increases relate to absorption, in vitro inhibitory potencies of these drugs against metformin transport by human organic cation transporter (OCT) 1, and the apical to basolateral absorptive permeability of metformin across Caco‐2 cells in the presence of therapeutic intestinal concentrations of cimetidine, trimethoprim or pyrimethamine, were determined. Whilst all inhibited OCT1, none enhanced metformin's absorptive permeability (~0.5 × 10−6 cm/sec) suggesting that DDI AUC changes are not related to absorption. Subsequently, to understand whether inhibition of renal transporters are responsible for AUC increases, in vitro inhibitory potencies against metformin transport by human OCT2, multidrug and toxin extrusion (MATE) 1 and MATE2‐K were determined. Ensuing IC 50 values were incorporated into mechanistic static equations, alongside unbound maximal plasma concentration and transporter fraction excreted values, in order to calculate theoretical increases in metformin AUC due to inhibition by cimetidine, trimethoprim or pyrimethamine. Calculated theoretical fold‐increases in metformin exposure confirmed solitary inhibition of renal MATE1 to be the likely mechanism underlying the observed exposure changes in clinical DDIs. Interestingly, clinically observed increases in metformin AUC were predicted more closely when the renal transporter fraction excreted value derived from oral metformin administration, rather than intravenous, was utilized in theoretical calculations, likely reflecting the “flip‐flop” pharmacokinetic profile of the drug.

Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium

Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor. In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments. A single dose of 100 μg glycopyrronium was inhaled alone and on Day 4 of a 6-day treatment with oral cimetidine 800 mg b.i.d. Trough plasma concentrations of cimetidine were determined throughout cimetidine dosing. Plasma concentrations and urinary excretion of glycopyrronium were determined up to 72 hours post glycopyrronium dose. The primary pharmacokinetics (PK) parameters were plasma peak concentration (Cmax), AUC up to the last measured concentration (AUClast), and renal clearance (CLr) of glycopyrronium. Cimetidine trough concentrations indicated that PK steady state of cimetidine was reached prior to single dose inhalation of glycopyrronium. Inhalation of glycopyrronium in the presence of cimetidine resulted in an increase in total systemic exposure (AUClast) of glycopyrronium by 22% (geometric mean ratio 1.22; 90% CI: 1.12 - 1.32). This exposure increase correlated with a slight decrease of 23% in CLr (geometric mean ratio 0.77; 90% CI: 0.70 - 0.85). Cmax was not affected. Both treatments were safe and well tolerated without any deaths or severe adverse events. Based on the magnitude of the PK changes seen in this study, no relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.

The antihistamine cimetidine alters invertebrate growth and population dynamics in artificial streams

Many pharmaceutical compounds have been detected in surface waters, but their effects on stream ecosystem function are not currently understood. Concentrations of cimetidine, a widely used antihistamine, have increased in streams and rivers. Invertebrates may be affected by exposure to cimetidine because they use histamines to regulate olfactory and stomatogastric function. Primary producers, such as algal biofilms, also may be affected by cimetidine, which may in turn, alter metabolism and ultimately invertebrate population dynamics. We conducted a long-term (83 d) experiment in artificial streams to measure the chronic effects of cimetidine on benthic biofilm function and stream invertebrate growth and population dynamics. We exposed 2 common invertebrate species, Gammarus fasciatus and Psephenus herricki, and biofilm to concentrations of cimetidine similar to what is found in USA surface waters (0.07–70.0 µg/L). We found no consistent effect of cimetidine on biofilm chlorophyll a or function (gross primary production, respiration). Growth and final biomass of reproducing G. fasciatus was reduced across all cimetidine treatments compared to the control. In addition, no individuals of the smallest size class occurred at lower concentrations of cimetidine suggesting that cimetidine may either more strongly affect invertebrates of smaller size classes or may suppress adult reproduction. We also found that higher concentrations of cimetidine significantly reduced survivorship of P. herricki. Low concentrations of cimetidine appear to have no effect on primary producers, but our observations indicate there are indirect negative effects on invertebrate growth and population dynamics.

The physiology of the normal human breast: an exploratory study

The physiology of the nonlactating human breast likely plays a key role in factors that contribute to the etiology of breast cancer and other breast conditions. Although there has been extensive research into the physiology of lactation, few reports explore the physiology of the resting mammary gland, including mechanisms by which compounds such as hormones, drugs, and potential carcinogens enter the breast ducts. The purpose of this study was to explore transport of exogenous drugs into ductal fluid in nonlactating women and determine if their concentrations in the fluid are similar to those observed in the breast milk of lactating women. We selected two compounds that have been well characterized during lactation, caffeine and cimetidine. Caffeine passively diffuses into breast milk, but cimetidine is actively transported and concentrated in breast milk. After ingestion of caffeine and cimetidine, 14 nonlactating subjects had blood drawn and underwent ductal lavage at five time points over 12h to measure drug levels in the fluid and blood. The concentrations of both caffeine and cimetidine in lavage fluid were substantially less than those observed in breast milk. Our results support recent evidence that the cimetidine transporter is not expressed in the nonlactating mammary gland, and highlight intriguing differences in the physiology and molecular transport of the lactating and nonlactating breast. The findings of this exploratory study warrant further exploration into the physiology of the nonlactating mammary gland to elucidate factors involved in disease initiation and progression.

Inhibition of Renal Alkaline Phosphatase by Cimetidine

Alkaline phosphatase (ALP) belongs to hydrolase group of enzymes. It is responsible for removing phosphate groups from many types of molecules, including nucleotides and proteins. Cimetidine (trade name Tagamet) is an antagonist of histamine H2-receptor that inhibits the production of gastric acid. Cimetidine is used for the treatment of gastrointestinal diseases. In this study the inhibitory effect of cimetidine on mouse renal ALP activity was investigated. Our results showed that cimetidine can inhibit ALP by uncompetitive inhibition. In the absence of inhibitor the V(max) and K(m) of the enzyme were found to be 13.7 mmol/mg prot.min and 0.25 mM, respectively. Both the Vmax and Km of the enzyme decreased with increasing cimetidine concentrations (0- 1.2 mM). The Ki and IC(50) of cimetidine were determined to be about 0.5 mM and 0.52 mM, respectively.

Ethanol-stimulated acid secretion in the isolated whole stomach of the rat.

The application of ethanol to the serosal surface of the isolated whole rat stomach stimulated a high rate of acid secretion, with a maximum response being obtained to 4% v/v ethanol. This acid response to ethanol was not inhibited by high concentrations (1 mM) of atropine or cimetidine, indicating that the response was probably not mediated by either histamine, gastrin or acetylcholine. These results using the secretory antagonists were confirmed by experiments in an isolated gastric mucosa preparation. The acid response to ethanol was significantly, but not completely inhibited by 10 mM thiocyanate, indicating the existence of an acid component of non-arietal cell origin in the mucosal bathing solution. However, analysis of the mucosal solution failed to reveal the presence of an acidic metabolite of ethanol.

In-vitro interaction between H2 antagonists and vecuronium.

The interaction between histamine H2 antagonists and the neuromuscular blocking drug vecuronium was investigated in the rat phrenic nerve-hemidiaphragm preparation. Cimetidine alone, in the concentration range 800-4000 microM produced between 14 and 74% neuromuscular paralysis with an EC50 (mean +/- s.e.) of 2900 +/- 100 microM. Ranitidine augmented the indirectly-evoked muscle response at concentrations between 30 and 160 microM but at higher concentrations, between 300 and 1800 microM, produced neuromuscular paralysis. Famotidine produced negligible and statistically insignificant (0-5%) neuromuscular paralysis at concentrations between 0.3 and 300 microM. Cimetidine (800 microM) shifted the neuromuscular concentration-effect curve of vecuronium to the left in a parallel manner, while ranitidine (160 microM) shifted it to the right. The potentiation ratio was 1.90 +/- 0.14 for cimetidine and 0.62 +/- 0.05 for ranitidine. Famotidine (30 microM) did not alter the response to vecuronium. These data indicate that higher than clinically relevant concentrations of cimetidine and ranitidine produce neuromuscular paralysis and may potentiate the action of vecuronium. Low concentrations of ranitidine may antagonize the action of vecuronium. Famotidine, in contrast, lacks significant neuromuscular effects.

Plasma Concentration-Response Relationship for Cimetidine Inhibition of Drug Metabolism in the Rat

Cimetidine inhibition of antipyrine elimination has been studied in the rat over a range of steady state cimetidine concentrations. Cimetidine is a potent inhibitor of antipyrine metabolism with a concentration of about 1.25 mg/liter causing a 50% decrease in the total plasma clearance of antipyrine. The degree of inhibition of antipyrine clearance caused by cimetidine is dependent upon its plasma concentration, but the relationship is not linear. The formation clearances of all antipyrine metabolites measured--3-hydroxymethylantipyrine, 4-hydroxyantipyrine, and norantipyrine--are inhibited by cimetidine at all concentrations used. The susceptibility of the different metabolites to cimetidine inhibition does vary. The renal clearance of antipyrine was also decreased by cimetidine by an unknown mechanism. Analysis of the individual formation clearances suggests that the inhibition of oxidative metabolism due to cimetidine is caused by its binding to two classes of enzyme sites--a high affinity, low capacity and a low affinity, high capacity site. These two different sites would appear to be responsible for the production of different metabolites of antipyrine. The true nature of the selectivity of cimetidine inhibition of antipyrine metabolism is apparent from the formation clearances but not from the urinary metabolite patterns.

Inhibition of colorectal cancer cell adhesion by cimetidine

Objective To investigate the effect of Cimetidine on the adhesion between colorectal cancer LOVO cells and endothelial ECV304 cells;and study whether Cimetidine can inhibit the expression of E-selectin in ECV304 cells. Methods Cellular uptake of rose Bengal stain was used to measure the adhesion between LOVO cells and ECV304 cells. Enzyme-linked immunosorbent assay(ELISA)and flow cytometry (FCM, indirect fluorescence staining and labeling)were used to detect the expression of E-selectin. Results ECV304 cells were exposed to different concentrations of Cimetidine. Both the adhesion between LOVO cells and ECV304 cells and the levels of E-selectin significantly decreased with increasing concentration of Cimetidine(P =0. 001 and 0. 001 respectively). Conclusion Cimetidine can inhibit the adhesion of human colorectal cancer LOVO cells on endothelial ECV304 cells by blocking E-selectin expression. Our observations indicated a potential of anti-adhesion therapy using Cimetidine in cancer treatment. Key words: Colorectal neoplasms; Endothelial cells; Neoplasms metastasis; Cimetidine

Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption

Abstract Objectives Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated. Methods Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics. Key findings The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration–time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure. Conclusions The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.

Spectrophotometric Determination of Cimetidine through Charge‐transfer Reaction with 1,5‐Dichloroanthraquinone as a π‐Electron Acceptor

AbstractCimetidine reacting with 1,5‐dichloroanthraquinone in acetone solution can produce a charge‐transfer complex that shows a strong absorption peak at 343 nm. The absorption value at 343 nm increased with cimetidine concentration in the range of 0.01–0.5 µg/mL, with regression coefficient of 0.9995 and detection limit of 0.006 µg/mL. This simple and sensitive method has been successfully applied to determine cimetidine in tablets and capsules, with average recovery of (98.47±0.92)% and (97.07±1.16)%, respectively. Furthermore, the mole ratio of the complex between cimetidine and 1,5‐dichloroanthraquinone is 2:1, and the mechanism of charge‐transfer reaction is explored.

Formulation and Evaluation of Cimetidine as a Topical Preparation

Cimetidine is a H2 – receptor blocking drug, widely used for the treatment of stomach ulcer in addition to its immune response modifying activity. This study is carried out to formulate cimetidine in a stable topical preparation.The in vitro release of cimetidine from different semisolid bases was studied utilizing: o/w emulsion base A and B, sodium carboxymethylcellulose gel, and w/o emulsion base. The results showed that the best release was obtained from the o/w emulsion base B (i.e. cream base); hence it was selected for extensive studies.The effect of cimetidine concentration on its diffusion through excised mouse skin was also investigated and the data showed an increase in the diffusion rate with increasing cimetidine concentration using cream base. The study also involved the diffusion of the drug from cimetidine 10% w/w cream base through excised mouse skin with different penetration enhancers utilizing: sodium lauryl sulphate, propylene glycol, xanthan gum, oleic acid, methyl salicylate, urea, and PEG1000. The study showed that 3% w/w sodium lauryl sulphate had a very highly significant effect on the diffusion rate of cimetidine. The study also showed that the temperature and the storage period led to a decrease in the diffusion rate, increase in the viscosity of cimetidine 10%w/w cream formula and a little change in the pH. The use of EDTA disodium 1.0%w/w as a stabilizer gave a more stable formula for cimetidine 10% w/w cream formula where the expiration date was 4.09 years compared to 2.74 years when using 1.0%w/w dl – α tocopherol as an antioxidant, and 1.35 years for the blank formula (i.e. formula free from antioxidant and stabilizer).Preliminary clinical study was performed among fifteen patients, ten with warts, and five with adrenal androgenic female – pattern alopecia. The results indicated that 80% of patients with warts gave positive response, while, 40% of patients with adrenal androgenic female – pattern alopecia gave positive response.

Convenient and rapid determination of cimetidine in human plasma using perchloric acid‐mediated plasma protein precipitation and high‐performance liquid chromatography

This study demonstrates the analysis of cimetidine in human plasma with HPLC using a simplified sample preparation by protein precipitation with perchloric acid. Plasma cimetidine concentration was determined by plotting peak height ratio of cimetidine to ranitidine (internal standard, IS) against cimetidine concentrations in plasma. The cimetidine and ranitidine peaks were completely separated and no interference from plasma was observed. The lower limit of quantification (LLOQ) of the method was established at 0.1 microg/mL with a precision of 4.3% and a relative error of 1.9%. The average analytical recovery was >90% over the range of cimetidine concentrations (0.1-15.0 microg/mL). The linearity of calibration curve was excellent (r(2) > 0.999). The within- and between-day precision and accuracy, expressed as the coefficients of variation and relative error, were found to be less than 5%. Compared with previously reported methods, the analytical technique for cimetidine determination in human plasma presented here demonstrates comparable accuracy and precision, an acceptable analysis time, shorter and simpler sample preparation, and a reduced need for complicated equipment. The method presented here is simple and rapid, and the precision and sensitivity are appropriate for the determination of cimetidine in plasma in pharmacokinetic studies.

Expression and Transport Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Dually Perfused Rat Placenta and HRP-1 Cell Line

Breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette transporter family that recognizes a variety of chemically unrelated compounds. Its expression has been revealed in many mammal tissues, including placenta. The purpose of this study was to describe its role in transplacental pharmacokinetics using rat placental HRP-1 cell line and dually perfused rat placenta. In HRP-1 cells, expression of Bcrp, but not P-glycoprotein, was revealed at mRNA and protein levels. Cell accumulation studies confirmed Bcrp-dependent uptake of BODIPY FL prazosin. In the placental perfusion studies, a pharmacokinetic model was applied to distinguish between passive and Bcrp-mediated transplacental passage of cimetidine as a model substrate. Bcrp was shown to act in a concentration-dependent manner and to hinder maternal-to-fetal transport of the drug. Fetal-to-maternal clearance of cimetidine was found to be 25 times higher than that in the opposite direction; this asymmetry was partly eliminated by BCRP inhibitors fumitremorgin C (2 microM) or N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918; 2 microM) and abolished at high cimetidine concentrations (1000 microM). When fetal perfusate was recirculated, Bcrp was found to actively remove cimetidine from the fetal compartment to the maternal compartment even against a concentration gradient and to establish a 2-fold maternal-to-fetal concentration ratio. Based on our results, we propose a two-level defensive role of Bcrp in the rat placenta in which the transporter 1) reduces passage of its substrates from mother to fetus but also 2) removes the drug already present in the fetal circulation.

Effects of the cimetidine on the biliary excretion of rosebengal in rats

Effect of the cimetidine on the biliary excretion of Rosebengal (RBG) was determined in rat after treatment with two different doses of cimetidine 80 mg/kg and/or 10mg/kg in aqueous solution administered intraperitoneally. Rosebengal (4mg/kg) was administered i.p. After treatment the excretion pattern of the effect of cimetidine on bile flow, plasma and liver were studied. The study showed that cimetidine at 80mg/kg increased the plasma concentration of RBG excreted up to 45min after administration while bile flow continued to increase even after 120 mini of treatment. At both concentrations of cimetidine there was a tendency in the direction of an increase in bile flew, plasma, liver weight and RBG liver concentrations, while there was decrease in RBG biliary excretion and RBG bile concentration. The excretion of RBG from hepatic cells in bile suggests that cimetidine has negative effect on the liver cells. Keywords: cimetidine, biliary excretion, bile flow, rosebengal Biokemistri Vol. 17(2) 2005: 101-106

A Conserved Glutamate Residue in Transmembrane Helix 10 Influences Substrate Specificity of Rabbit OCT2 (SLC22A2)

OCT1 and OCT2 are involved in renal secretion of cationic drugs. Although they have similar selectivity for some substrates (e.g. tetraethylammonium (TEA)), they have distinct selectivities for others (e.g. cimetidine). We postulated that "homolog-specific residues," i.e. the 24 residues that are conserved in OCT1 orthologs as one amino acid and in OCT2 as a different one, influence homolog-specific selectivity and examined the influence on substrate binding of three of these conserved residues that are found in the C-terminal half of the rabbit orthologs of OCT1/2. The N353L and R403I substitutions (OCT2 to OCT1) did not significantly change the properties of OCT2. However, the E447Q replacement shifted substrate selectivity toward an OCT1-like phenotype. Substitution of glutamate with cationic amino acids (E447K and E447R) abolished transport activity, and the E447L mutant displayed markedly reduced transport of TEA and cimetidine while retaining transport of 1-methyl-4-phenylpyridinium. In a novel homology model of the three-dimensional structure of OCT2, Glu(447) was found in a putative docking region within a hydrophilic cleft of the protein. In addition, six residues identified in separate studies as exerting significant effects on OCT binding were also found within the putative cleft region. There was a significant correlation (r(2) = 0.82) between the IC(50) values for inhibition of TEA transport by 14 different compounds and their calculated K(D) values for binding to the model of rabbit OCT2. The results suggest that homology modeling offers an opportunity to direct future site-directed studies of OCT/substrate interaction.

Effect of selected alcohol dehydrogenase inhibitors on human hepatic lactate dehydrogenase activity — anin vitro study

Metabolic acidosis severely complicates methanol and ethylene glycol intoxications. Acidosis is caused by acid metabolites and can be intensified by lactate elevation. Lactate concentration depends on the NADH(2)/NAD ratio. Lactate dehydrogenase (LDH, E.C.1.1.1.27.) supplies more lactate when the level of NADH(2) is elevated. The aim of the study was to evaluate the effect of alcohol dehydrogenase (ADH) inhibitors and substrates: cimetidine, EDTA, 4-methylpyrazole (4-MP), Ukrain and ethanol on LDH activity. The activity of LDH was determined spectrophotometrically in human liver homogenates incubated with cimetidine, EDTA, 4-MP and Ukrain at concentrations of 2 x 10(-6), 10(-5) and 5 x 10(-5) m as well as ethanol at concentrations of 12.50, 25.00, 50.00 mm. The LDH activity was significantly increased by 10(-5) and 5 x 10(-5) m concentrations of cimetidine and 4-MP, and by all concentrations of ethanol. The most effective change of LDH activity of about 26% (P<0.01) was observed at the highest concentration of ethanol. Ukrain inhibited LDH activity at both concentrations, i.e. 10(-5) and 5 x 10(-5) m (P<0.05). However, EDTA did not significantly influence LDH activity. The data showed that ethanol and 4-MP, the main antidotes in methanol or ethylene glycol poisoning, may increase liver LDH activity - an undesirable effect during the therapy of patients intoxicated with these alcohols. On the other hand, the decrease of LDH activity in the presence of Ukrain is a promising finding but definitely requires further investigation.

타가메트정 400 mg에 대한 신일시메티딘정 400 mg의 생물학적동등성시험

Cimetidine is a histamine antagonist, used for the treatment of endoscopically or radiographically comfirmed duodenal ulcer, pathologic GI hypersecretory conditions, and active, benign and gastric ulcer. Simple method for determining cimetidine in human plasma has been developed and validated. The analytical procedure for cimetidine showed a linear relationship in the concentration ranges from . Coefficient of variance (CV, %) for intraday and interday validation and relative error (RE, %) were less than . Based on this analytical method, the bioequivalence of two cimetidine 400 mg tablets, reference (Tagamet 400 mg) and test drug (Sinil CIMETIDINE 400 mg) was evaluated according to the guidelines set by the Korea Food and Drug Administration (KFDA). Release of cimetidine from the tablets in vitro was tested using KP VIII Apparatus II with various dissolution media (pH 1.2, 4.0, 6.8 buffer solutions and water). Twenty-four healthy volunteers, years in age and in body weight, were divided into two groups and a randomized cross-over study was performed. After oral administration of a tablet containing 400 mg of cimetidine, blood samples were taken at predetermined time intervals and concentrations of cimetidine in plasma were determined using HPLC equipped with UV detector. The dissolution profiles of the two tablet formulations were very similar at all dissolution media. In addition, pharmacokinetic parameters such as and were calculated and ANOVA was employed for the statistical analysis of parameters. The results were revealed that the differences in and between the two tablets were 4.17 % and 0.97% respectively. At 90% confidence intervals, the differences in these parameters were also within . All of the above mentioned parameters have met the criteria of KFDA guidelines for bioequivalence, indicating that the test drug tablet (Sinil CIMETIDINE tablet) is bioequivalent to Tagamet 400 mg tablet.