The effect of three H2 receptor antagonists on the disposition of cyclosporin a in the in situ perfused rat liver model

The in situ, perfused rat liver model was used to investigate the effect of three H₂ receptor antagonists on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H₂-receptor antagonist-treated groups) of male Sprague-Dawley rats (300–350 g). All animals received CyA, 2.5 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg), or famotidine (0.4 mg). Perfusated and bile samples were collected and assayed for CyA, AM1, and the H₂ receptor antagonists by HPLC. Results indicated that CyA perfusate concentrations in the controls and cimetidine and ranitidine-treated groups were not significantly different, although levels in the famotidine group were significantly higher at all times (p<0.05), except 30 min, compared to the controls. However, examination of the AM1 perfusate and bile data and the apparent metabolic clearance data indicated that CyA metabolism was still occurring, despite the presence of the H₂ receptor antagonist. It is suggested that the absence of a interaction may be attributed to a lack of specificity of the H₂ receptor antagonists for CYP3A, the isoenzyme responsible for CyA metabolism.     

Comparative effects of H2-receptor antagonists on subjective and objective assessments of sleep

Background: Clinically, it is common for patients to experience drowsiness in association with consumption of H₂receptor antagonists. Reported side-effects with H₂-receptor antagonists include insomnia and somnolence. The present study was designed to assess and compare the effects of three H₂-receptor antagonists (cimetidine, famotidine, and ranitidine) on nocturnal and daytime sleepiness. Methods: This is a double-blind crossover study on 12 normal volunteers. Subjects were studied under conditions of placebo, cimetidine (400 mg b.d.), famotidine (20 mg b.d.), and ranitidine (150 mg b.d.) for one week. Sleep was assessed at the end of each one-week interval via polysomnographic evaluation conducted on nights 6 and 7 of drug administration. On the day between the two nights in the sleep laboratory, a multiple sleep latency test was conducted. Results: The results revealed a significant reduction in the sleep onset latency with famotidine administration, but since there were no effects of any of the medications in the multiple sleep latency test, this finding is of dubious clinical significance. Cimetidine revealed a small increase in subjective estimates of sleepiness. No effects on sleep-related respiratory parameters were noted. Conclusions: This study demonstrates the lack of effect of peripheral administration of H₂-receptor antagonists on sleep stages, while subjective or objective assessment of daytime alertness revealed small effects of famotidine and cimetidine.     

Comparative Evaluation of the Hemodynamic Effects of Oral Cimetidine,Ranitidine, and Famotidine as Determined by Echocardiography

Study Objective . To evaluate the influence of cimetidine, ranitidine, famotidine, and placebo on cardiac performance as determined by echocardiography. Design . Randomized, four-way crossover trial. Setting . Echocardiography laboratory at a university hospital. Participants . Twelve healthy volunteers. Interventions . Volunteers received oral treatment with placebo, cimetidine 800 mg, ranitidine 300 mg, or famotidine 40 mg once/day for 7 days. Measurements and Main Results . On the seventh day of each study phase, 2 hours after administration of the final dose, each subject underwent cardiac echocardiography and Doppler flow studies. No significant differences were detected in ejection fraction, peak flow velocity, or percentage fractional shortening among the treatment phases. A large degree of variability in ejection fraction was observed, with some subjects experiencing marked decreases. Conclusion . The histamine-2 (H₂)-receptor antagonists had no effect on the hemodynamic variables as determined by echocardiography. The variability in the hemodynamic response may in part explain the conflicting results reported in the literature. It also raises the question as to whether certain individuals are more sensitive to the potential cardiac effects of H₂-receptor antagonists.     

Drug interaction studies of H2-receptor antagonists with mefloquine, pyrimethamine and sulfadoxine

Fansimef is a new antimalarial schizontocide that contains mefloquine, pyrimethamine, and sulfadoxine with a weight ratio of 1:20:10. This antimalarial combination is highly active against multidrug-resistant strains of Plasmodium falciparum. H₂-receptor antagonists (cimetidine, famotidine, and ranitidine) are reversible competitive blockers of histamine at H₂-receptor and do not affect the H₁-receptor. These are potent inhibitors of all phases of gastric acid secretion. They do so by binding to H₂-receptors on the parietal cells of stomach. The effect of various dissolution mediums with respect to pH on these drug–drug interactions and in vitro availability reveals that availability of antimalarial drugs increased to a smaller extent in the presence of H₂-receptors. The influence of temperatures on these interactions has been examined to elucidate the mechanism of these interactions. Antimalarial drugs could be administrated concurrently with H₂-receptor antagonist (cimetidine and famotidine); however, ranitidine should not be given because availability was almost suppressed in the presence of antimalarial drugs.     

Intestinal Uptake of Cimetidine and Ranitidine in Rats

The H₂-receptor antagonists exhibit unusual absorption behavior in that double peaks often occur after oral administration. Moreover, administration with some high potency antacids decreases the extent of absorption. To date, no explanation that can completely account for these observations has been advanced. One problem is that there is a lack of consensus as to the mechanism of absorption of the H₂-receptor antagonists from the gastrointestinal tract. In the studies reported here, the mechanism and regional dependence of intestinal uptake of two H₂-receptor antagonists, cimetidine and ranitidine, were investigated in rats using the in vitro everted ring technique. The uptake rate of cimetidine from both jejunum and colon was linear with concentration (in the range of 0.0005-40 mM), and there was no significant competition for uptake in the presence of the structurally similar H₂-receptor antagonists, famotidine and ranitidine. In the case of ranitidine too, the uptake rate from the jejunum and colon was linear with concentration (in the range of 0.0005-5 mM), and there was no competition for uptake by either famotidine or cimetidine. These data indicate that uptake of cimetidine and ranitidine in the rat jejunum and colon occurs by a predominantly passive process. Both cimetidine and ranitidine exhibited regional differences in uptake rate. Uptake tended to be greatest in the ileum, similar in duodenum and jejunum, and lowest in the colon. However, differences in uptake rates between locations in the small intestine appeared to be too modest to account for the double peak behavior of either compound.     

Low-dose famotidine and effervescent cimetidine in healthy subjects: a placebo-controlled overnight pH study

Background:

Amongst the low-dose H₂-receptor antagonists available for the self-medication of dyspepsia, both famotidine 10 mg and cimetidine 200 mg have been shown to raise intragastric pH, but there is a delay after ingestion before significant effects can be demonstrated. A new effervescent preparation of cimetidine 200 mg releases an acid buffer which has a more rapid effect on intragastric pH.

Aim:

To investigate the relative abilities of low-dose famotidine and effervescent cimetidine to raise intragastric pH after a single postprandial evening dose.

Methods:

Twenty-four healthy subjects (12 men, 12 women, median age 32 years) completed a three-period crossover trial of famotidine 10 mg, effervescent cimetidine 200 mg and placebo. After a standard meal was given at 18.30 h to subjects fasted for 5.5 h, drug or placebo was given at 19.30 h. Intragastric pH was recorded with combined glass electrodes from 18.00 to 07.30 h by digital recorders.

Results:

Over the 12 h post-dose period the mean area under the pH/time curve (AUC ) after famotidine 10 mg was 3.73, after cimetidine 200 mg effervescent 2.79, and after placebo 2.07. Over the same period the median pH and percentage of time that recordings were above pH 3 were 3.45 and 52.5 after famotidine 10 mg, 2.40 and 33.8 after cimetidine 200 mg effervescent, and 1.68 and 15.9 after placebo. Both active treatments were significantly different from placebo by each measure (P < 0.001), and famotidine 10 mg was significantly more effective than cimetidine 200 mg effervescent by each measure over the 0–12 h period (P < 0.001). Comparisons of mean AUCs for each 15 min period after dosing showed that decrease in acidity was significantly greater after cimetidine 200 mg effervescent than after famotidine 10 mg for the first 60 min. In the later post-dose period only famotidine 10 mg raised pH for all time points to 12 h, whilst the effect of effervescent cimetidine 200 mg was detectable to ≈ 8 h.

Conclusions:

Inhibition of gastric acidity over the 12 h post-dose period was significantly greater and endured longer after famotidine 10 mg than after effervescent cimetidine 200 mg, but for the 60 min period immediately after dosing the effect on intragastric pH was significant following effervescent cimetidine 200 mg but not famotidine 10 mg. This suggests effervescent formulations of H₂-receptor antagonists with an acid buffer have a more rapid effect on intragastric pH than film-coated tablets.

     

A Comparison of the Cholinergic Activity of Selected H2-Antagonists and Sulfoxide Metabolites

Famotidine and selected H₂-antagonists were evaluated with respect to toxicity and selected pharmacological activities. When administered intraperitoneally to mice at a dose equivalent to 10 times their respective H₂-antagonist ED₅₀ values, no deaths were observed. Similarly, no alteration in brain ACh concentrations or overt pharmacological effects were noted. However, at 400 mg/kg, ranitidine produced 89% lethality, followed by cimetidine (11%) and famotidine. Only cimetidine and famotidine at this dose significantly elevated brain acetylcholine levels. These results do not correlate with the in vitro data, where ORF-17578 and ranitidine were the most potent entities with respect to acetylcholinesterase inhibition (1–2 × 10^–6 M), followed by nizatidine > cimetidine > famotidine. The sulfoxide metabolites of ranitidine and cimetidine were approximately one-tenth as potent as their parent compounds with respect to inhibition of acetylcholinesterase. Direct muscarinic stimulation or potentiation of acetylcholine-induced contraction in ileal tissue was not observed for any of the H₂-antagonists.     

The inhibition of first-pass metabolism of ethanol by H2-receptor antagonists: a tabulated review

Introduction: In the 1980s–1990s numerous studies were performed on H₂-receptor antagonist inhibition of ethanol first-pass metabolism. Blood alcohol concentrations warranting possible driving under the influence citations in the United States have subsequently dropped from ≥100 mg/dL to 50 mg/dL (Utah in 2019) (30 mg/dL or zero tolerance in some parts of the world). A reexamination of these studies seemed important.

Areas covered: Papers were compiled that addressed the effect of cimetidine, ranitidine, famotidine, and nizatidine on ethanol metabolism first from a PubMed search and then from citations within these papers. Studies were tabulated for fasting versus fed, ethanol and H₂-receptor antagonist dose and a summary of pharmacokinetic changes.

Expert opinion: At doses of 0.15–0.30 mg/kg in the postprandial state (primarily after breakfast), the H₂-receptor antagonists: cimetidine, ranitidine, famotidine, and nizatidine have all been found to increase the first-pass metabolism of ethanol. With cimetidine, there were sufficient studies to suggest it might be inhibitory outside these restricted states. While the role of inhibition of alcohol dehydrogenase has not been clearly defined, there is circumstantial evidence to support this mechanism. Further studies are required to elucidate the ability of H₂-receptor antagonists to inhibit first-pass metabolism of ethanol.     

Effect of an evening dose of regular and effervescent formulations of ranitidine or cimetidine on intragastric pH in healthy volunteers

Aims: To compare the effects on intragastric acidity of a single evening dose of either standard or effervescent formulations of ranitidine (300 mg) or cimetidine (800 mg). Methods: Twelve healthy subjects were studied, using a four-period randomized cross-over design and an ambulatory intragastric pH monitoring technique. The subjects received a standard evening meal at 17.00 hours and one of the H₂-receptor antagonist formulations was given at 23.00 hours. Results: Both effervescent formulations caused a transient rapid increase in intragastric pH, reaching a maximum at about 3 min after ingestion. After both effervescent formulations a significantly higher pH was measured during the first 45 min after ingestion (P < 0.05), compared to the regular formulations. The onset of action of the H₂ receptor antagonists was similar for both formulations of ranitidine and the effervescent cimetidine, but tended to be slower for the regular cimetidine (P= 0.06). Nocturnal intragastric pH was significantly increased by all four formulations, but more effectively so by the two ranitidine formulations. The duration of action (taken as time with pH > 4) of both ranitidine formulations was longer than that of both cimetidine formulations (P < 0.002). Conclusions: A single evening dose of 300 mg ranitidine produces a stronger decrease of nocturnal gastric acid secretion than 800 mg cimetidine. The effervescent formulations of both drugs offer the advantage of a rapid decrease (within minutes) of intragastric acidity, with preservation of the sustained systemic effect.     

Ranitidine and cimetidine; drug interactions with single dose and steady-state nifedipine administration.

The effect of ranitidine 300 mg once daily and cimetidine 800 mg once daily on the disposition of nifedipine was studied in two groups of 12 volunteers. Both investigations were placebo-controlled cross-over studies. The first group received ranitidine, cimetidine or placebo for 5 days with 20 mg nifedipine given on the 5th day. Each period was separated by 1 week. The second group received nifedipine 10 mg three times daily for 5 days together with the H2-receptor antagonist or placebo. Cimetidine produced a significant increase in the AUC of both single and steady state dosing of nifedipine. Peak nifedipine levels were significantly increased only in the chronic dose study compared to placebo. Ranitidine did not produce any significant changes in either study.     

In vitro interaction studies of diltiazem with H2 receptor antagonists

Diltiazem is a well-known cardiovascular drug that is used clinically for the treatment of angina pectoris and hypertension. H₂-receptor antagonists are used to treat gastroesophageal reflux, gastric and duodenal ulceration. In vitro interaction studies of diltiazem with H₂-receptor antagonists (cimetidine, ranitidine, and famotidine) were investigated by using spectrophotometric and RP-HPLC techniques. The availability of diltiazem was found to be influenced considerably in presence of H₂-receptor antagonists. The effect of various dissolution mediums, simulating body environments with respect to pH on these interactions was examined to elucidate the mechanism of these interactions. Moreover, diltiazem-H₂ receptor complexes were synthesized to confirm the interaction of these drugs. The complexes formed were then characterized by IR spectroscopy and verified by computational molecular modeling.     

Lack of effect of certain histamine H2-receptor blockers on the glucuronidation of 7-hydroxy-4-methylcoumarin by human liver microsomes.

Contrary to the general belief that cimetidine and ranitidine spare glucuronidation of drugs, some authors have indicated that both cimetidine and ranitidine could inhibit the glucuronidation of paracetamol (acetaminophen) by cultured rat hepatocytes. Thus, we tested the effect of three histamine H2-receptor blockers (cimetidine, ranitidine and famotidine) on the glucuronidation of 7-hydroxy-4-methylcoumarin (7-OH-4-MC) by human liver microsomes. None of the drugs studied produced significant inhibition of the glucuronidation of 7-OH-4-MC when used at concentrations up to 1.5 mM. Thus, even the new H2-receptor blocker, famotidine, spares glucuronidation. These findings further support the previous reports which suggest that glucuronide conjugation in humans is spared by H2-receptor blockers.     

Comparison of famotidine with cimetidine and ranitidine

The pharmacodynamic, therapeutic, and toxicologic properties of famotidine are evaluated and compared with those of cimetidine and ranitidine. Famotidine, an H2-receptor antagonist with a thiazole nucleus, is approximately 7.5 times more potent than ranitidine and 20 times more potent than cimetidine on an equimolar basis. Therapeutic trials indicate that famotidine 20 mg b.i.d. or 40 mg at bedtime is as effective as standard doses of cimetidine and ranitidine for healing duodenal ulcers. A dose of 40 mg at bedtime appears to heal benign gastric ulcers. A single nocturnal dose of 20 mg is effective in preventing duodenal ulcer relapse. Further studies are required that compare the efficacy of famotidine with cimetidine and ranitidine in the treatment of gastric ulcers and in the prevention of recurrent duodenal ulcers. The overall incidence of adverse effects observed with famotidine appears to be similar to that reported for cimetidine and ranitidine. Like ranitidine, famotidine does not have antiandrogenic effects or substantially inhibit the hepatic metabolism of drugs. Because of its increased antisecretory potency and lack of antiandrogenic effects at higher doses, famotidine may be the H2-receptor antagonist of choice in treating Zollinger-Ellison syndrome. Additional clinical experience, as well as cost and safety factors, will determine the place of famotidine in treating and preventing acid-peptic disorders.     

Comparative effects of H2-receptor antagonists on drug interaction in rats

The most widely used H2-receptor antagonist, cimetidine, is known to interact with cytochrome P-450 drug-metabolizing enzymes and, therefore, interacts with other drugs which may be administered concurrently. In this study, effects of three H2-receptor antagonists, famotidine, ranitidine, and L-643,441, on drug interaction were studied using cimetidine as a positive control. Cimetidine and L-643,441, but not famotidine or ranitidine, prolonged antipyrine elimination and hexobarbital-induced sleeping time. The effect of cimetidine and famotidine on the anticoagulant effect on warfarin in rats was also investigated. Pretreatment of rats with cimetidine produced a significant depression of plasma prothrombin complex activity, whereas concomitant administration of famotidine did not alter the plasma prothrombin complex activity. Whereas cimetidine is known to impair the elimination of a number of drugs metabolized by microsomal mixed function oxidase enzyme systems, the results of the present study suggest that famotidine and ranitidine have little effect on these enzyme systems.     

The Cardiovascular Effects of Thyrotropin-Releasing Hormone (TRH) are Attenuated by Cimetidine in Rats

Abstract: The modulation of cardioventilator effects of thyrotropin-releasing hormone (TRH) by histaminergic mechanisms was studied in anaesthetized rats pretreated with histamine receptor antagonists. TRH (1–10. nmol/kg) into the lateral cerebral ventricle dose-dependently elevated mean arterial pressure, heart rate and stimulated respiration. The respiratory stimulating effect of TRH remained unchanged after pretreatments with histamine H₁-receptor antagonist diphenhydramine or H₂-receptor antagonists cimetidine and ranitidine, while the TRH-induced hypertension and tachycardia were attenuated by cimetidine. This antagonism was not due to an interation between TRH and cimetidine at their central binding sites, since there was no displacement of [³H]MeTRH binding in the presence of cimetidine nor did TRH displace [³H]cimetidine in rat brain homogenates. Inability of diphenhydramine to modify the cardiovascular effects of TRH indicates that these effects are not due to histamine liberation, as cardiovascular stimulation after central administration of histamine is mainly mediated via H₁-receptors. The antagonism of the cardiovascular responses to TRH by cimetidine was not due to blockade of H₂-receptors, since another potent H₂-receptor antagonist ranitidine was unable to affect the cardiovascular effects of TRH. Therefore, we suggest that cimetidine exerted antagonism of TRH by some non-specific action.     

Effect of mifentidine on mepirizole-induced duodenal ulcer in the rat

The H2-receptor antagonists mifentidine, famotidine, cimetidine and ranitidine were examined for their ability to prevent the duodenal ulcer caused by mepirizole (250 mg/kg p.o.), a non-steroidal anti-inflammatory agent, in the conscious rat. All the compounds exerted a dose-related protective effect and on the basis of their ED50s, the following rank order of potency was found: mifentidine = famotidine greater than ranitidine greater than cimetidine. The antiulcer activity displayed by the H2-receptor antagonists evaluated in this model reflects their potency in inhibiting basal and stimulated gastric acid secretion in rat. The results of these studies indicate mifentidine as a potent anti-ulcer agent.     

Synthesis and Histamine H2-Receptor Antagonist Activity of 4-(1-Pyrazolyl)butanamides,Guanidinopyrazoles, and Related Compounds

A series of 4-(1-pyrazolyl)butanamides, pyrazolylalkyl cyanoguanidines, and related compounds with diverse functional groups (e.g. nitro, amino, guanidino groups) in the 3-position of the pyrazole ring was prepared via 4-(3-nitro-1-pyrazolyl)butanenitrile ( 5 ) and the corresponding carboxylic acid 7 as central intermediates. The amides 9a – d were prepared from the primary amines 8a – d which represent partial structures of the H₂-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine. The roxatidine-derived 4-(3-nitro-1-pyrazolyl)butanamide ( 9a ) proved to be the compound with the highest H₂-receptor antagonist activity of 23 compounds tested at the isolated guinea pig right atrium preparation, achieving about 6 times famotidine's or 160 times cimetidine's potency. By contrast, in Ghosh-Schild rats 9a did not inhibit histamine-stimulated gastric acid secretion at a dosage of 0.1 μmol/kg i.v. Compounds 20a (the 3-(trifluoroethylguanidino)pyrazole analogue of 9a, 12a (the cyanoguanidine analogue) and N-{4-[3-(trifluoroethylguanidino)-1-pyrazolyl]butyl}cyanoguanidine ( 29 ), which are about as active as famotidine in the atrium, turned out to be very potent inhibitors of gastric acid secretion as well (e.g., 29 : 74 % inhibition at 0.025 μmol/kg). These compounds are comparable to famotidine in the rat stomach and by far superior to cimetidine and ranitidine in this test system.     

Famotidine,a new H2-receptor antagonist,does not affect hepatic elimination of diazepam or tubular secretion of procainamide

Summary In 8 healthy male volunteers the pharmacodynamic responses to a single dose of diazepam and a single dose of procainamide were assessed before and after pre-treatment with the H₂-receptor antagonist famotidine in a randomized crossover study. The pharmacokinetics of diazepam and procainamide were also studied, and the binding of famotidine to human liver microsomes was also measured. Cimetidine induced binding changes with a spectral dissociation constant (K_s) of 0.87 mM, whereas famotidine produced no measurable spectral alteration in concentrations up to 4 mM. The elimination half-life (t_1/2: 45.6 h) and total plasma clearance (CL: 0.28 ml/min/kg) of diazepam were not significantly altered by famotidine (t_1/2=39.0±11.4 h; CL =0.31±0.08 ml/min/kg). Similarly, there was no enhancement of the sedative effect of diazepam by famotidine. The pharmacodynamics and pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), too, were not significantly changed by famotidine: procainamide t_1/2 2.9 vs 3.0 h under famotidine and renal clearance (CL_R) 436 vs 443 ml/min; and NAPA CL_R 195 vs 212 ml/min under famotidine. The data suggest that famotidine, in contrast to cimetidine, does not affect the pharmacokinetics of diazepam (hepatic elimination) or procainamide (tubular secretion). This new H₂-receptor antagonist appears to be devoid of an interaction potential for either type of drug elimination.     

In-vitro potencies of histamine H2-receptor antagonists on tetraethylammonium uptake in rat renal brush-border membrane vesicles

Abstract— The histamine H₂ antagonists cimetidine, ranitidine and famotidine are organic bases that are cleared from the body by active renal tubular secretion involving the organic cation transporter in the proximal tubule. To determine the potential for competition for the transporter between these drugs and other drugs, their inhibitory potencies were assessed in-vitro, using rat renal brush-border membrane vesicles and tetraethylammonium as the substrate. The concentration-dependent effect of cimetidine, ranitidine and famotidine on the 15-s proton-stimulated uptake of tetraethylammonium into the membrane vesicles was studied using five different rat kidneys. The order of inhibition potencies was: cimetidine (mean IC50= 1·07 μm ) > famotidine (2·43 μm ) > ranitidine (55·4 μm ). The results indicate the potential for drug interactions in the kidney, especially for cimetidine and famotidine.     

Effect of some new histamine H2-receptor antagonists on the guinea-pig papillary muscle

Summary Several histamine H₂-receptor antagonists (cimetidine, ranitidine, oxmetidine and tiotidine) were tested for their activity on the papillary muscle of the guinea pig stimulated by histamine. All of the compounds exerted a competitive antagonism against histamine the order of potency being tiotidine > oxmetidine > ranitidine > cimetidine. Oxmetidine was the only drug which at high concentrations (10^–6 M) decreased the maximum response of histamine probably because of non specific effects of the molecule already described in the literature. As it was expected, the H₁-receptor antagonist, mepyramine, exerted a non-competitive antagonism.