Cimetidine Concentrations Research Articles

Solid Dosage Form Analysis by near Infrared Spectroscopy: Comparison of Reflectance and Transmittance Measurements Including the Determination of Effective Sample Mass

Investigations into the near infrared analysis of intact tablets allow comparison of the reflectance and transmittance methodologies. The studies involved estimation of the effective sample mass and the effect of sample inhomogeneities. An empirical method for determining effective sample mass used tablets of varying thickness and constant compression force. Tablets containing a range of cimetidine concentrations were used to study the effect of drug concentration on effective sample mass as a function of wavelength of observation. Effective sampling depth was between 1.9 and 2.7 mm for reflectance measurements. With transmittance measurements, signal was completely attenuated when tablet thickness was greater than 3.4–4.9 mm, depending on the wavelength of observation. Multi-layered tablets provided a means of probing the effect of sample inhomogeneity. Both reflectance and transmittance measurements may be sensitive to sample inhomogeneity. Transmittance measurements are sensitive to pathlength variations.

Cimetidine enhances the plasma praziquantel concentration and treatment efficacy against Microcotyle sebastis in cultured rockfish Sebastes schlegeli.

The effect of cimetidine on the praziquantel concentration in the blood of the rockfish Sebastes schlegeli and the consequent effect on the treatment efficacy against Microcotyle sebastis were investigated. Fish were divided into 7 groups and orally administered praziquantel alone (200 and 100 mg kg(-1) body weight [BW]) or in combination with cimetidine (in doses of 200, 100 or 50 mg kg(-1) BW cimetidine with a praziquantel dose of 100 mg kg(-1) BW). The fish in the sixth group were coadministered 50 mg praziquantel and 200 mg cimetidine kg(-1) BW. The fish in the control group were administered only saline. At 24 h post-treatment, the plasma was analyzed for praziquantel by reversed-phase high-performance liquid chromatography (RP-HPLC) using diazepam as the internal standard, and the gills were examined to confirm the effectiveness of each treatment. The praziquantel concentration in plasma of fish administered 100 mg praziquantel + 200 mg cimetidine kg(-1) BW was not significantly different from that of fish treated with 200 mg praziquantel kg(-1) BW and was significantly (p < 0.05) higher (about 2 times) than that of fish administered 100 mg praziquantel kg(-1) BW. The group of fish administered 50 mg praziquantel + 200 mg cimetidine kg(-1) BW showed a similar plasma praziquantel concentration to that in the fish treated with 100 mg praziquantel kg(-1) BW. The treatment efficacies of the groups of fish coadministered 100 mg praziquantel kg(-1) BW and various concentrations of cimetidine (200, 100 and 50 mg kg(-1) BW) were not significantly different from that of the group of fish administered 200 mg praziquantel kg(-1) BW, but were significantly higher than those of the groups of fish fed 100 mg praziquantel kg(-1) BW alone or coadministered 50 mg praziquantel + 200 mg cimetidine kg(-1) BW.

Interaction of cimetidine with equine hemoglobin.

Interaction of cimetidine with equine hemoglobin.

Influence of lysine on cimetidine uptake and on excretion of cimetidine by the rat mammary gland.

Cimetidine is actively transported into human and rat milk. However, the transporters involved have not been characterized. It is possible that xenobiotics may be actively transported into milk by an amino acid transport system. The objective of these studies was to determine the influence of lysine on the uptake of cimetidine into rat mammary explants (study 1), and on the excretion of cimetidine into rat milk (study 2). In study 1, excised lactating rat mammary epithelial tissue fragments were exposed to 3H-cimetidine and 14C-lysine in the presence of 10 microM, 1 mM, or 1 M cold lysine, and the uptake of 3H-cimetidine and 14C-lysine were measured by liquid scintillation counting after 5 or 20 minutes of incubation. After 5 minutes of incubation, 1 M lysine inhibited 3H-cimetidine uptake by 47.7% (SD +/- 6.5%), compared with 10 microM lysine (P < 0.05), and 14C-lysine uptake was also inhibited by 54.1% (SD +/- 6.4%) (P < 0.05). Similar results were seen after 20 minutes of incubation. In a randomized crossover study (study 2), 6 lactating female rats were infused to steady state with cimetidine (0.5mg/h) in the presence or absence of lysine (360mg/h). Cimetidine concentrations in serum and milk were determined by high-performance liquid chromatography. Cimetidine systemic clearance (28.6+/-15.0mL/kg/min vs. 38.9+/-3.9 mL/kg/min, mean +/- SD) and milk to serum cimetidine ratio (M/S) (28.0+/-16.1 vs. 28.9+/-6.7), respectively, were not significantly altered by the presence or absence of lysine. Although 1 M lysine inhibited uptake of cimetidine in rat mammary explants, the concentrations of lysine used in this study, which approached toxicity in vivo, produced no significant effects on cimetidine transport into milk or the systemic clearance of cimetidine.

Pharmacokinetics of intravenous and intragastric cimetidine in horses. I. Effects of intravenous cimetidine on pharmacokinetics of intravenous phenylbutazone.

Cimetidine was administered intravenously and by the intragastric route to six mares at a dose of 4.0 mg/kg of body weight (bw). Specific and sensitive high performance liquid chromatographic methods for the determination of cimetidine in horse plasma and urine and cimetidine sulfoxide in urine are described. Plasma cimetidine concentration vs. time data were analysed by non-linear least squares regression analysis to determine pharmacokinetic parameter estimates. The median (range) plasma clearance (Cl) was 8.20 (4.96-10.2) mL/min.kg of body weight, that of the steady-state volume of distribution (Vdss) was 0.771 (0.521-1.15) L/kg bw, and that of the terminal elimination half-life (t1/2 beta) was 92.4 (70.6-125) minutes. The median (range) renal clearance of cimetidine was 4.08 (2.19-6.23) mL/min.kg bw or 55.4 (36.3-81.8)% of the corresponding plasma clearance. Cimetidine sulfoxide was excreted in urine and its urinary excretion through 8 h accounted for 12.0 (9.8-16.6)% of the plasma clearance of cimetidine. The median (range) extent of intragastric bioavailability was 14.4 (6.82-21.8)% and the maximum plasma concentration after intragastric administration was 0.31 (0.24-0.50) microgram/mL. Intravenous cimetidine had no effect on the disposition of intravenous phenylbutazone or its metabolites except that the maximum plasma concentration of gamma-hydroxyphenylbutazone was less after cimetidine treatment.

Neurotoxic Convulsions Induced by Histamine H2Receptor Antagonists in Mice

Convulsive potency was evaluated to investigate the mechanism of neurotoxic convulsion induced by histamine H2receptor antagonists (H2blockers). Four H2blockers, cimetidine (721–1236 nmol), ranitidine (477–954 nmol), famotidine (7.4–44 nmol), and nizatidine (226–603 nmol) were administered intracerebrally (ic) to mice. Dose dependency of clonic and/or tonic convulsion was observed, and the ED50 values of convulsive occurrence for cimetidine, ranitidine, famotidine, and nizatidine were 997, 662, 23.4, and 404 nmol, respectively. Intraperitoneal pretreatment of muscimol, aminooxy acetic acid, diazepam, (±)2-amino-7-phosphonoheptanoic acid (APH), or (+)MK801 suppressed the tonic convulsion after ic administration of ranitidine, but had no effect on clonic convulsion. Furthermore, the convulsive threshold concentration in the brain determined by constant rate infusion of ranitidine was not affected by the pretreatment of muscimol, diazepam, APH, and MK801. ED50 values for convulsive occurrence after ic administration of four H2blockers correlated well with the EC50 values for gastric acid secretion inhibition. The convulsive threshold concentrations of cimetidine and ranitidine in the brain were 11 and 2.5 μM, respectively, which were similar to the dissociation constants determined from the inhibition of gastric acid output in mice. From these results, tonic convulsion induced by H2blockers can be suppressed by GABAergic or glutamatergic anticonvulsants, while clonic convulsion induced by H2blockers may be associated with the blockade of H2receptor in the brain and not be directly associated with the GABA and glutamate-mediated neurotransmission.

Applications and simulations of a discontinuous oral absorption pharmacokinetic model.

To illustrate the application of a discontinuous oral absorption model to cimetidine and ranitidine plasma concentration versus time data to demonstrate the use of the model for drugs which display discontinuous oral absorption profiles, and to illustrate the effect of various model parameters on plasma drug concentration versus time profiles and bioavailability. A discontinuous oral absorption model was used to fit ranitidine and cimetidine serum concentrations following oral and intravenous administration. The model was also used to simulate bioavailability and plasma concentrations versus time profiles for various parameter values. Serum concentrations following administration of ranitidine and cimetidine were well described by the model, and parameter estimates obtained were in agreement with literature values. Simulations demonstrate the effects of various absorption parameters and gastroin-testinal tract transit parameters on bioavailability and plasma concentration profiles. This discontinuous oral absorption pharmacokinetic model can be a useful tool in characterizing absorption phases, disposition, and bioavailability of drugs exhibiting two absorption peaks following oral administration.

Effect of acute renal failure on neurotoxicity of cimetidine in rats.

We investigated the effect of acute renal failure on the neurotoxicity of cimetidine in rats. Experimental acute renal failure was produced by bilateral ureteral ligation. Cimetidine was intravenously infused to ureter ligated (UL) and control rats, and cimetidine concentration in plasma, brain and cerebrospinal fluid (CSF) were compared. The cimetidine concentration in plasma was rapidly increased in UL rats as compared to control rats. The cimetidine concentration in CSF at the onset of convulsion did not depend on the infusion rate, suggesting that cimetidine in CSF equilibrates rapidly with the site of action for clonic convulsion. The cimetidine concentration in CSF of UL rats at the onset of clonic convulsion was lower than those of control rats. Increased sensitivity to the drug on the central nervous system may contribute to increased toxicity of cimetidine with renal failure.

Renal disposition and drug interaction screening of (-)-2'-deoxy-3'-thiacytidine (3TC) in the isolated perfused rat kidney.

Dideoxynucleoside bases are used for the treatment of acquired immune deficiency syndrome (AIDS), acting by inhibiting reverse transcriptase and preventing human immunodeficiency virus (HIV) replication. Currently, AZT (zidovudine), ddC (zalcitibine), and ddI (didanosine) are available to the medical community to prevent the onset of AIDS in HIV-infected individuals. 3TC (-)-2'-deoxy-3'-thiacytidine, lamivudine), a new dideoxynucleoside base, is currently undergoing Phase II/III trials, and has exhibited anti-HIV replication activity, a favorable adverse event safety profile, and is eliminated via renal mechanisms. Concomitantly administered drugs could potentiate the effects of 3TC due to interaction in the kidney. An isolated perfused rat kidney (IPK) technique was used to screen several clinically relevant drugs for potential interaction with 3TC. The following perfusions were performed: baseline 3TC; and 500 ng/mL 3TC with clinically relevant concentrations of AZT, ddC, ddI, probenecid, trimethoprim, sulfamethoxazole, ranitidine, and cimetidine. Renal clearance of 3TC was nonlinear between 500 and 5000 ng/mL, decreasing from 3.06 to 1.74 mL/min. Excretion ratio also decreased, from 3.67 (500 ng/mL) to 2.49 (5000 ng/mL), consistent with a decrease in 3TC secretion. AZT, ddI, and ddC elicited no or minimal effects on 3TC elimination at the concentrations studied. However, trimethoprim caused significant reductions in 3TC elimination parameters: clearance and excretion ratio decreased to 1.25 mL/min and 1.43, respectively. These results indicate that caution should be exercised when the combination of 3TC and trimethoprim are administered to AIDS patients.

Cimetidine Pharmacodynamics and Pharmacokinetics in Healthy Subjects: A Comparison of Tablets and Suspension

The objective of this study was to compare the effect of cimetidine 200 mg tablet with that of cimetidine suspension (200 mg/10 mL), a 20 mL suspension of 800 mg magnesium hydroxide and 912 mg aluminum hydroxide, and matching placebo on intragastric pH of healthy volunteers. There were 13 males and seven females, mean age 23 years (range 20 to 32) and mean weight 72 kg (range 55 to 89). The intragastric pH of each subject was measured over 6 h starting immediately before dosing on each of five study days. Cimetidine plasma levels were measured for 6 h after dosing on each of the cimetidine study days. Cimetidine tablet and suspension were superior to placebo tablet or suspension or to the magnesium hydroxide/aluminum hydroxide suspension in the area under the pH time curve from 0 to 6 h, percentage time pH of at least 3.5, change from pretreatment pH area under the pH time curve (0 to 6 h) and maximum increase in pH. Mean plasma cimetidine levels were significantly and positively correlated to mean intragastric pH for both cimetidine tablets and cimetidine suspension. Comparing cimetidine concentration (Cmax) and lower percentage time plasma cimetidine concentration was at least 0.5 μg/mL (the minimum therapeutic level). These pharmacokinetic variations between cimetidine suspension and tablets may have partially explained the pharmacodynamic differences of the lower area under the pH time curve (0 to 6 h). The results indicate that both cimetidine tablets and cimetidine suspension significantly increase intragastric pH relative to the magnesium hydroxide/aluminum hydroxide suspension, placebo tablets or placebo suspension. Based on the assumption that elevation of intragastric pH is an important factor for alleviation of the symptoms and for the healing of peptic disorders, the results of this study suggest that both cimetidine tablets and cimetidine suspension should be effective treatment.

Secretagogue-induced [14C]aminopyrine uptake in isolated equine parietal cells

Summary Equine oxyntic mucosal cells were obtained by sequential exposure to pronase and collagenase. Acid production by parietal cells was assessed by uptake of [14C]aminopyrine (ap), a weak base that accumulates in intracellular acidic spaces. Incubation for various times revealed a maximal ap uptake at 10 minutes for histamine and carbachol. Similar secretagogue responses were observed for parietal cells from the mucosal cell preparation or after enrichment by elutriation. Histamine and isobutyl-methylxanthine (ibmx) stimulated AP uptake with a dose-dependent response and maximal effective concentration of 100 μM. Carbachol, 1 to 100 μM, and pentagastrin (pg), 1 to 1,000 μM, were ineffective stimulants of ap uptake. The ap uptake values for 100 μM ibmx, 1 μM carbachol, or 100 nM pg were 77 ± 6%, 50 ± 3-2%, and 40 ± 4.5%, respectively, of that observed with maximal stimulation by 100 μM histamine (mean ± sem, n = 4 to 14). Uptake of ap by nonstimulated control cells was 36 ± 3.6% of maximal histamine stimulation. The ap accumulations during control conditions and after stimulation with 100 μM histamine and IBMX, 1 μM carbachol, or 100 nM pg were 1.18 ± 0.39, 2.81 ± 0.85, 1.93 ± 0.48, 1.44 ± 0.36, and 1.23 ± 0.33 pmol of ap/105 parietal cells, respectively. Individual histamine dose-response curves were shifted to the right by increasing ranitidine and cimetidine concentrations (0.1 to 50 μM). These results indicate that isolated equine parietal cells are maximally stimulated by histamine and minimally stimulated by carbachol and pg.

Cimetidine and omeprazole do not affect cyclosporine disposition by the rat liver.

Cyclosporine has been used with increased frequency, occasionally in conjunction with cimetidine and omeprazole. The present study was undertaken to study a possible interaction between either of the two drugs and cyclosporine in the liver. The isolated perfused rat liver was used with recirculation of perfusate for 150 min. 6 experiments were performed with each of the following: cyclosporine alone, cyclosporine with cimetidine, and cyclosporine with omeprazole. Initial concentrations of cyclosporine, cimetidine and omeprazole were 600 micrograms/ml, 12.5 micrograms/ml, and 4.5 micrograms/ml, respectively. At 1 and 2 h of perfusion 1 micrograms of omeprazole was added to perfusate. Cyclosporine concentration was determined at 30 min intervals. Results at 150 min expressed as percentage of the initial concentration of cyclosporine were 59 +/- 3%, 55 +/- 6%, and 60 +/- 9% for cyclosporine alone, with cimetidine and with omeprazole, respectively. The elimination rate of cyclosporine by the liver did not change during the entire experiment with the addition of cimetidine or omeprazole. Thus, it is concluded that short administration of cimetidine or omeprazole will not affect cyclosporine metabolism by the liver.

Anti-oxidant properties of H 2-receptor antagonists : Effects on myeloperoxidase-catalysed reactions and hydroxyl radical generation in a ferrous-hydrogen peroxide system

Ulcerogenesis of the gastroduodenal mucosa is caused by the digestive action of gastric juice and initially involves an inflammatory reaction with infiltration of phagocytes. The anti-inflammatory activity of many drugs have been attributed to the inhibition of the leukocyte enzyme, myeloperoxidase (MPO). In this study, the H 2-antagonists in clinical use were found to be potent inhibitors of MPO-catalysed reactions ( IC 50 < 3 μ M) under conditions resembling those in experiments with intact neutrophils. Since peak plasma concentrations of cimetidine, ranitidine and nizatidine are well within the micromolar range, after oral therapeutic dosing, our results may be of clinical relevance. The inhibitory actions of cimetidine and nizatidine were largely due to scavenging of hypochlorous acid (HOC1), a powerful chlorinating oxidant produced in the MPO-H 2O 2-Cl − system. In contrast to famotidine, ranitidine was also a potent scavenger of HOCl, while both drugs inhibited MPO reversibly by converting it to compound II, which is inactive in the oxidation of Cl −. The HOCl scavenging potencies of ranitidine and nizatidine were about three times higher than that of the anti-rheumatic drug, penicillamine, which had a potency similar to that of cimetidine. The rapid HOCl scavenging ability of penicillamine is thought to contribute to its anti-inflammatory effects. Using riboflavin as a probe, the H 2-antagonists were found to be inhibitors of hydroxyl radical (·OH) generated in a Fe 2+-H 2O 2 reaction mixture. Spectral analyses of the interaction of iron ions with the drugs and studies with chelators, suggest that the drugs were efficient chelators of Fe 2+, in addition to their ·OH scavenging abilities. Since the gastrointestinal tract can contain potentially reactive iron, the simultaneous presence of H 2-antagonists may help to suppress iron-driven steps in tissue damage.

Comparative Effects of Cimetidine and Famotidine on the Vagally Stimulated Acid Secretion in the Isolated Mouse Whole Stomach

We investigated the effects of cimetidine and famotidine on the acid secretory response to electrical vagal stimulation, bethanechol and histamine in the isolated mouse whole stomach preparation. The acid secretion elicited by electrical vagal stimulation at the position of the esophagus (10 Hz, 0.3 msec, 10 V for 5 min) was reproducible by repeated stimulation in each preparation, and it was abolished by tetrodotoxin, atropine and hexamethonium. This vagally stimulated acid secretion was abolished by cimetidine (3 mM), while it was only partly inhibited by famotidine (10-100 microM). Histamine (100 microM)-induced acid secretion was inhibited by cimetidine and famotidine, and the doses of these drugs required for complete inhibition were 3 mM and 10 microM, respectively. In contrast, bethanechol (10 microM)-induced acid secretion was slightly reduced by famotidine (1-100 microM), but markedly reduced by cimetidine (3 mM). In the guinea pig ileum, millimolar concentrations of cimetidine and famotidine shifted the dose-response curve of the contractile response to acetylcholine rightward. These findings suggest that the inhibitory effect of cimetidine on the vagally stimulated or bethanechol-induced acid secretion is elicited at least partly through mechanisms different from H2-antagonism.

Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate

Creatinine clearance inaccurately estimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. We studied the ability of oral cimetidine, a blocker of tubular creatinine secretion, to improve the accuracy of measuring creatinine clearance.Clearances of inulin and endogenous creatinine were simultaneously measured in 16 patients with renal disease before administration of cimetidine and during 8 successive 3 h clearance periods with cimetidine 400 mg as priming dose followed by 200 mg every 3 h. At baseline, creatinine relative to inulin clearance (ClC/ClI) ranged from 1·14 to 2·27. With cimetidine, ClC/ClI approached unity in 8 patients (mean 1·02 [SD 0·03]), but considerably exceeded unity in 8 others (1·33 [0·14]). Plasma cimetidine/ creatinine ratio was smaller in this second group, due to significantly higher renal clearance of cimetidine (333 [136] vs 165 [89] ml/min, p=0·01). In a further study, cimetidine dose and, consequently plasma cimetidine concentration, was increased in 6 additional patients who had incomplete inhibition previously. This increased dose completely inhibited tubular creatinine secretion in the third until the sixth hour, so that creatinine clearance equalled GFR. Provided an adequate dose of cimetidine is given, 24 h creatinine clearance during administration of drug measures G FR accurately in patients with renal disease. However, because of the maximum daily dose of cimetidine that is advised, short clearance times (3 h) are recommended.

Effects of Exposure to Standard- and Nicotine-Reduced-Cigarette Smoke on Pharmacokinetics of Theophylline and Cimetidine in Rats

Influences of exposure to standard- (containing nicotine and tar) and nicotine-reduced-cigarette smoke on the pharmacokinetics of theophylline (20 mg/kg, per os) and cimetidine (50 mg/kg, per os) were investigated in rats. Animals were exposed to standard- or nicotine-reduced-cigarette smoke for 8min with a “smoking machine”. In control rats, theophylline concentrations in plasma increased rapidly, peaked 2h later, and then decreased gradually. Concentrations of theophylline in plasma of rats exposed to standard- and nicotine-reduced-cigarette smoke were suppressed in comparison with that of control rats, and the suppressive effect of nicotine-reduced-cigarette smoke was weaker than that of standard-cigarette smoke. The suppression of theophylline concentrations in plasma induced by exposure to cigarette smoke may be due to nicotine and other constituents of the cigarette smoke, even if the effects are slight. For cimetidine, no difference was found between drug concentration in plasma of rats exposed to nicotine-reduced-cigarette smoke and that of control rats; however, the drug concentration in plasma of rats exposed to standard-cigarette smoke was markedly suppressed. These results suggest that the suppression of cimetidine concentrations in plasma may be due solely to nicotine in cigarette smoke.

Interaction between succinylcholine and cimetidine in rats.

The hypothesis that histamine H2 receptor blockade adversely affects neuromuscular function was tested, in vivo, in rats anaesthetised with urethane during mechanical pulmonary ventilation. Succinylcholine was administered as a bolus and constant-rate infusion to maintain 49.2% (+/- 1.5 SEM) twitch suppression in 19 rats. Cimetidine iv, 3.2, 7.5, 10, 17.8, 23.7, 31.6, or 56.2 mg.kg-1 was then administered in groups of two to three rats. Cimetidine produced an immediate potentiation of twitch suppression followed by a transient reversal and then a continued potentiation. Peak potentiation occurred within 19.0 (+/- 2.7) sec and was maintained in 11 rats at steady-state. Reversal was evident 4.1 (+/- 0.4) min after cimetidine administration. There was a good relationship between peak potentiation and serum cimetidine concentration with 50% potentiation occurring at 46.5 (+/- 4.6) micrograms.ml-1. Potentiation at steady-state was not correlated to serum cimetidine concentration but there was a weak relationship between reversal and serum cimetidine concentration. These results support reports from patients of an interaction between cimetidine and succinylcholine.

Stability and compatibility of methylprednisolone sodium succinate and cimetidine hydrochloride in 5% dextrose injection

The stability and compatibility of methylprednisolone sodium succinate in admixtures with cimetidine hydrochloride in 5% dextrose injection were determined. Admixtures containing methylprednisolone sodium succinate, in concentrations equivalent to methylprednisolone 0.4 or 1.25 mg/mL, and cimetidine 3 mg/mL (as the hydrochloride salt) were prepared in 5% dextrose injection 100 mL. Control solutions containing each drug alone at the same concentrations were also prepared. The admixtures were prepared in triplicate and were kept in polyvinyl chloride infusion containers at controlled room temperature (24 degrees C). Immediately after mixing and at 2, 4, 8, 12, and 24 hours, samples were removed and visually inspected, measured for pH, and assayed by stability-indicating high-performance liquid chromatography to determine the concentrations of methylprednisolone 21-succinate ester and cimetidine. No visual evidence of incompatibility was noted either with the unaided eye or a microscope. No substantial changes in pH occurred over the study period. The addition of cimetidine decreased the pH of the methylprednisolone sodium succinate control solutions from about 7.3 to about 5.6. The concentrations of methylprednisolone 21-succinate ester and cimetidine in both test and control solutions did not change significantly over the 24-hour study period. Methylprednisolone sodium succinate, in concentrations equivalent to methylprednisolone 0.4 and 1.25 mg/mL, was chemically stable and visually compatible in admixtures with cimetidine 3 mg/mL (as the hydrochloride salt) in 5% dextrose injection 100 mL at 24 degrees C for 24 hours.

Compatibility of cefoperazone sodium and cimetidine hydrochloride in 5% dextrose injection

The compatibility of cimetidine hydrochloride and cefoperazone sodium in 5% dextrose injection stored at two temperatures was studied. Cimetidine hydrochloride and cefoperazone sodium were reconstituted or diluted with 5% dextrose injection to form an admixture with a cimetidine concentration of 2 mg/mL and a cefoperazone concentration of 5 mg/mL. The admixture was stored in 100-mL vented i.v. containers in the dark at 4 and 25 degrees C; three containers were stored at each temperature. A 2-mL sample was taken from each container after 0.5, 0.75, 1, 6, 12, 24, and 48 hours of storage and visually inspected, tested for pH, and assayed by a stability-indicating high-performance liquid chromatographic method. Triplicate studies were done for each storage condition. At both temperatures, drug concentrations varied by less than 5% during the study period. No color change, precipitation, or cloudiness was observed for any of the solutions under any of the storage conditions. Cefoperazone sodium 5.0 mg/mL and cimetidine hydrochloride 2.0 mg/mL in admixtures in 5% dextrose injection are stable for 48 hours at 4 and 25 degrees C.

Cimetidine and omeprazole have different effects on hepatic extraction of lidocaine in rats

The effect of two antisecretory drugs, omeprazole and cimetidine, on the hepatic extraction of indocyanine green and lidocaine was studied in the isolated perfused rat liver. Both indocyanine green and lidocaine are removed by the liver with high extraction efficiency in a flow-dependent manner. The elimination of lidocaine, but not indocyanine green, involves metabolism by the mixed-function oxidase in the liver. A selective effect on the hepatic extraction of lidocaine, but not indocyanine green, may therefore indicate an inhibition of hepatic mixedfunction oxidase. To test this hypothesis, a nonrecycling system at a fixed perfusion flow rate was used to measure the extraction of lidocaine. Under control conditions, the extraction rate of lidocaine was 83% ± 8%. In the presence of omeprazole at concentrations of 0.9, 2.0, and 4.5μgmL, the extraction rates were 81% ± 9%, 82% ± 7%, and 75% ± 7%, respectively. These changes were not significantly different than control rates. In contrast, the increasing concentrations of cimetidine caused significant decreases in the hepatic extraction of lidocaine to values of 78% ± 8%, 63% ± 14%, and 48% ± 14% at concentrations of 0.25, 0.50 and 1.25 μg/mL, respectively. The hepatic extraction of indocyanine green, 39% ± 6%, was not affected by the administration of either omeprazole or cimetidine. Thus, in the rat, omeprazole seems to be a less potent inhibitor of cytochrome P-450 than cimetidine.