Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00568 (Cimetidine)
 1,659 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 1978, less than two years after its release, published reports indicated that cimetidine caused an increased prothrombin time in patients receiving warfarin. It has since been established that cimetidine inhibits the hepatic metabolism of at least 15 other drugs. The time course for the interaction is rapid with the onset and termination detectable within the first day of starting or stopping cimetidine. In vitro and clinical data indicate that the interaction is dependent upon the cimetidine dose or plasma concentration, but its limits are not well defined. Cimetidine inhibits the metabolism of drugs that are primarily eliminated by the hepatic mixed-function oxidase, microsomal enzymes. The degree to which cimetidine decreases drug clearance is dependent upon the fraction of drug eliminated by the inhibited metabolic routes, the route of administration for high hepatic extraction drugs, and the patient's characteristics. Cimetidine decreases the clearance of various drugs from 20-60%. The interpatient variability in the effects of cimetidine for any given drug can be considerable. Since cimetidine and ranitidine have been reported to decrease indocyanine green clearance, it has been assumed that H2-antagonists decrease functional hepatic blood flow. However, there is direct and indirect evidence indicating there is not a significant effect on liver blood flow. At similar therapeutic doses, ranitidine does not decrease the clearance of theophylline, phenytoin, diazepam, propranolol, ethanol, antipyrine, and aminopyrine. Ranitidine does not alter the prothrombin time in subjects receiving warfarin. Differences between cimetidine and ranitidine on drug metabolism appear to exist both because the cytochrome P-450 binding affinity for ranitidine is about 10 times lower than cimetidine and because the daily ranitidine dose is 1/4 that of cimetidine. The imidazole ring and lipophilicity of cimetidine are characteristics that favor inhibition of drug metabolism. Since both cimetidine and ranitidine change the gastric pH and fluid volume, there is the potential for altering drug absorption. Drug distribution does not appear to be influenced by either agent. Although neither cimetidine nor ranitidine significantly alters the glomerular filtration rate, their influence on renal drug elimination is not well characterized. The numerous case reports of therapeutic failure primarily from drug toxicity are basically due to cimetidine inhibition of metabolism. This cimetidine effect (and lack of ranitidine effect) may help explain differences in the adverse effect profiles between cimetidine and ranitidine and may be important for a number of uninvestigated drugs.
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PMID:The pharmacokinetic basis for H2-antagonist drug interactions: concepts and implications. 614 Feb 86

Histamine H2-antagonists have the ability to produce fundamental changes in the absorption and disposition of other drugs. However, there are similarities and differences between the H2-antagonists in this respect, depending on the process involved. By increasing the intragastric pH any H2-antagonist has the potential of altering the absorption of weak acids or weak bases. However, since the rise in intragastric pH is not immediate, as with antacids, this type of interaction might be avoided for concomitantly administered, rapidly absorbed drugs. Whereas cimetidine inhibits hepatic mixed-function oxidase drug metabolism, ranitidine does not have this characteristic. Clinical studies have found that cimetidine produces a 20 to 60 percent decrease in the clearance of 23 drugs (such as warfarin, theophylline, quinidine, phenytoin, imipramine, propranolol, nifedipine). Marketed and investigational H2-antagonist drugs differ in their ability to inhibit drug metabolism due to the combined characteristics of cytochrome P-450 binding affinity and therapeutic dosage. Cimetidine also inhibits the renal-tubular secretion of other weak bases (such as procainamide). Management suggestions are presented to help clinicans predict and avoid failure in drug therapy as a result of these drug interactions.
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PMID:Histamine H2-antagonist drug interactions in perspective: mechanistic concepts and clinical implications. 615 Jun 39

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on theophylline pharmacokinetics and to determine whether the previously described cimetidine-theophylline interaction is dose dependent. Twelve healthy adult men were given a 6-mg/kg intravenous aminophylline dose on four occasions. Subjects were randomly assigned four treatments: no treatment (control); cimetidine, 1,200 mg/day; cimetidine, 2,400 mg/day; and ranitidine, 300 mg/day. Cimetidine, 1,200 mg/day, significantly decreased theophylline clearance by 36% (range, 22% to 49%) and increased the mean elimination half-life from 5.7 hours (control) to 9.2 hours. A significant difference was not found between the two cimetidine dosages, indicating dose independence of the interaction over the dosage range studied. Ranitidine did not significantly alter theophylline pharmacokinetics. Theophylline plasma protein binding was not affected by any treatment. The relative effects of cimetidine and ranitidine on the elimination of cytochrome P-450 metabolized drugs such as theophylline indicate a useful property of ranitidine as compared with cimetidine.
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PMID:Inhibition of theophylline clearance by cimetidine but not ranitidine. 632 9

Most reports of interactions involving analgesics deal with their effects on the actions of other drugs rather than vice versa. Aspirin and ethanol have synergistic effects on the development of gastritis, gastrointestinal bleeding, and chronic gastric ulcer. This must be the most common and most important interaction affecting analgesic toxicity. Combined overdosage of aspirin with central nervous system depressants may be particularly hazardous because suppression of the salicylate-induced respiratory stimulation further shifts the disordered acid-base balance towards acidosis. The toxicity of acetaminophen (paracetamol) depends primarily on the balance between the rate of formation of the hepatotoxic metabolite and the rate of glutathione synthesis in the liver. In animals, prolonged pretreatment with ethanol increases the metabolic activation and acute toxicity of acetaminophen, and there is some evidence that chronic alcoholics are more susceptible to hepatotoxicity following acute overdosage. It has been assumed that this sensitivity in chronic alcoholics is due to microsomal enzyme induction with enhanced metabolic activation of acetaminophen. However, the metabolic activation of acetaminophen, as judged by the urinary excretion of its cysteine and mercapturic acid conjugates, is not increased in heavy drinkers or in patients induced by long-term treatment with anticonvulsants or rifampicin. Microsomal enzyme induction is complex. There are important species differences and different agents may selectively induce different variants of the multiple forms of cytochrome P-450. The acute administration of ethanol greatly reduces the metabolic activation of acetaminophen in heavy drinkers with more than a 50 percent decrease in cysteine and mercapturic acid conjugate production. Thus ingestion of ethanol should reduce the risk of liver damage following acetaminophen overdosage. Cimetidine, which inhibits the oxidative metabolism of some drugs, reduces the hepatotoxicity and increases the dose of acetaminophen in mice required to kill 50 percent of the animals. However, contrary to expectations, cimetidine does not inhibit the oxidative metabolism of acetaminophen in man. Salicylamide competes with acetaminophen for sulphate conjugation but is unlikely to potentiate toxicity following overdosage since sulphate conjugation is rapidly saturated anyway. Animal studies suggest that the hepatotoxicity of acetaminophen after overdosage may be increased by other agents which deplete glutathione, but there is no information on this point in man.
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PMID:Drug interactions affecting analgesic toxicity. 635 60

Cimetidine interaction with cytochrome P-450 may reduce binding affinity of some drugs, causing reduced metabolism of substrates such as diazepam and warfarin. Isoniazid also inhibits hepatic mixed function oxidase activity and has been reported to depress circulatory levels of hydroxylated vitamin D metabolites. Because hepatic vitamin D 25-hydroxylase is considered to be a cytochrome P-450-dependent enzyme, we examined the effect of cimetidine and isoniazid on hepatic vitamin D 25-hydroxylase activity in vitro in the rat. The assay system employed whole liver homogenates from rats deficient in vitamin D and chromatographic separation of radiolabeled substrate and product. Cimetidine and isoniazid were incubated with liver homogenates prior to the addition of 12 nmol/L final concentration of tritiated vitamin D. In addition, assays were performed in rats deficient in vitamin D given cimetidine or isoniazid 1 hour before sacrifice. Both cimetidine and isoniazid inhibited vitamin D 25-hydroxylase activity in vitro. Vitamin D 25-hydroxylase activity was depressed to 75%, 65%, and 55% of control values by cimetidine at 3, 6, and 10 mmol/L concentrations, respectively, and to 81%, 53%, and 35% by isoniazid at 1, 5, and 10 mmol/L. In vivo intraperitoneal administration of 120 mg/kg cimetidine depressed vitamin D 25-hydroxylase activity by 22%, and the same dose of isoniazid inhibited activity by 26%. The effect of long-term cimetidine therapy on vitamin D metabolism requires further evaluation.
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PMID:Hepatic vitamin D 25-hydroxylase inhibition by cimetidine and isoniazid. 648 Dec 17

Cimetidine is a well known inhibitor of the heme-containing enzyme cytochrome P-450. We have found that it also inhibits delta-aminolevulinic acid synthase (ALA-S) and microsomal heme oxygenase, the rate-limiting enzymes for heme synthesis and heme degradation respectively. Cytochrome P-450 content was decreased but microsomal heme concentration remained unaltered for a period of 30 min after in vivo cimetidine administration to rats. In vitro incubation of cimetidine with each of the above enzymes revealed no direct effect of cimetidine on ALA-S but about 50% inhibition of heme oxygenase and 20% reduction in cytochrome P-450 content. This suggests that a metabolite of cimetidine inhibits ALA-S activity in vivo, while the drug itself or a metabolite inhibits heme oxygenase both in vivo and in vitro. A rise in ALA-S activity seen after its early inhibition and its return to approximate control values after 60 min suggest a reversible inhibition of ALA-S by a metabolite of cimetidine and may correspond to its clearance from the animal. An elevation in microsomal heme content paralleled the rise in ALA-S activity while microsomal heme oxygenase activity returned to only 65% of control value 60 min after cimetidine treatment. Cytochrome P-450 content did not change after its initial decrease, suggesting that irreversible alteration had occurred.
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PMID:Effect of cimetidine on delta-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver. 654 9

We studied the effect of cimetidine on liver and kidney heme metabolism and on the activity of the cytochrome P-450 drug metabolizing enzyme system. Results show that the induction of a heme biosynthetic enzyme and the activities of two drug metabolizing enzymes are impaired when cimetidine is given in combination with phenobarbital (PB). When rats were given four 33 mg doses of cimetidine IP per day for 2 days and sacrificed, we found no significant effect on kidney or liver delta-aminolevulinic acid (ALA) synthase activity. Heme oxygenase and cytochrome P-450 levels were also unchanged in these tissues. In contrast, when we measured activities of certain liver drug metabolizing enzymes, it was found that cimetidine significantly inhibited aniline hydroxylase and aminopyrine-N-demethylase by 43% and 65%, respectively. The observed changes in the activities of these drug metabolizing enzymes led us to study cimetidine in combination with other drugs. When the porphyric inducing agent allylisoprophyacetamide (AIA) was administered alone, we found a 326% increase in hepatic ALA synthase activity at 16 hours. Cimetidine given together with AIA increases hepatic ALA synthase 291 and 300% at 16 and 20 hour intervals respectively. Cytochrome P-450 levels in AIA treated rats with or without cimetidine were decreased to 52-65% of control values without a significant change in heme oxygenase levels. When PB was given alone, we found an increase in hepatic ALA synthase activity by 223 and 400% at 16 and 20 hour intervals, respectively. Cimetidine in combination with PB at the same time intervals showed a slightly diminished increase of hepatic ALA synthase activity by 146 and 238%, respectively. When PB was given alone, hepatic cytochrome P-450 was increased 96% at 16 hours, whereas when combined with cimetidine a similar increase of hepatic cytochrome P-450 was observed. In conclusion cimetidine does not significantly alter the action of the porphyric agents PB and ALA on cytochrome P-450; however, combined administration of PB plus cimetidine does impair the induction of ALA synthase. Additionally, cimetidine markedly decreased the drug metabolizing enzymes aniline hydroxylase and aminopyrine-N-demethylase in vivo, and subsequently may interfere with the endogenous metabolism of other drugs.
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PMID:Pharmacologic toxicity of cimetidine on hepatic and renal drug metabolism. 654 43

In 15 normal men, cimetidine taken orally in a dose of 300 mg twice a day for 3 days reduced to similar extents the rate constants for formation (ki) of the three principal metabolites of antipyrine (AP): 29.9% +/- 8.5% (mean +/- SD) for 4-hydroxyantipyrine (4-OH-AP); 28.3% +/- 6.3% for 3-hydroxymethylantipyrine (3-OHM-AP); and 22.4% +/- 5.6% for N-demethylantipyrine (NDM-AP). AP clearance declined 24.3%; AP salivary t 1/2 rose 33%; and corrected AP apparent volume of distribution was unchanged. In one apparently normal subject, however, kis for formation of 3-OHM-AP and NDM-AP rose after cimetidine even though AP clearance declined 19.7%. This surprising result, which suggests that cimetidine can exert an inductive effect on the hepatic mixed-function oxidases of some subjects, was checked by restudying the individual. Very similar values occurred on repetition. The average increase in kis for NDM-AP and 3-OHM-AP was 172.2% and 34.0%. These unusual results in this subject indicate that at least two distinguishable forms of cytochrome P-450 participate in AP metabolism in man. Cimetidine appeared to reduce the amount of AP absorbed from the gut in 10 of our 15 normal subjects.
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PMID:Cimetidine-induced reduction in gastrointestinal absorption of antipyrine and rate constants for formation of its metabolites. 671 70

Propofol is rapidly cleared from the body by biotransformation; however, the repercussions of changes in cytochrome P-450 activity on propofol rate of elimination are unknown. To assess how changes in cytochrome P-450 activity affect propofol kinetics, one group of rabbits (N = 6) was pretreated with cimetidine, another (N = 6) had an inflammatory reaction produced by the subcutaneous injection of turpentine, and a third one (N = 6) was subjected to mild hypoxia. Propofol was infused (0.3 mg/min/kg) for 40 min; multiple blood samples were withdrawn before and once the infusion was stopped to assess propofol blood kinetics. Cimetidine did not modify propofol kinetics. An inflammatory reaction prolonged propofol half-life without changing significantly its clearance or volume of distribution. Hypoxia decreased propofol clearance and as a consequence, its half-life increased. Parallel studies were conducted in vitro, where propofol metabolism was documented in liver and lung homogenates prepared from controls (N = 6), and from rabbits that were pretreated with cimetidine (N = 3), had an inflammatory reaction (N = 5), or were hypoxic (N = 6). In controls, the lung biotransformed propofol as rapidly as the liver, and both organs generated an unidentified polar metabolite. Cimetidine did not affect the in vitro metabolism of propofol. The inflammatory reaction reduced the in vitro rate of elimination of propofol and, as a consequence, the production rate of the metabolite was also decreased in liver and lung homogenates. Hypoxia diminished hepatic metabolism of propofol but did not influence that in lung homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo and in vitro effect of cimetidine, inflammation, and hypoxia on propofol kinetics. 809 29

A number of compounds, as exemplified by verapamil and desipramine, have been shown to enhance the susceptibility of resistant malaria parasites to chloroquine. The mechanism by which these agents reverse resistance is still controversial but is though to involve alterations in drug transport causing an increase in steady-state drug concentrations. We have proposed that an alternative resistance mechanism may involve the metabolic deactivation of the drug in some resistant parasites via cytochrome P-450 mixed-function oxidases. If the hypothesis is true, it should be possible to alter drug susceptibility in malaria parasites by the use of agents known to inhibit or induce cytochrome P-450 activities. We have assessed the ability of known inhibitors of cytochrome P-450 enzymes (cimetidine, metyrapone, and alpha-naphthoflavone) to enhance chloroquine susceptibility in Plasmodium falciparum culture-adapted and wild-type isolates in vitro and P. berghei in vivo. In all three systems, the inhibitor cimetidine enhanced parasite susceptibility to chloroquine, and this increase in susceptibility was unrelated to changes in chloroquine steady-state concentrations in vitro or to alterations in host pharmacokinetics in vivo. Additionally, the cytochrome P-450 inducer phenobarbital produced slight decreases in P. falciparum drug susceptibility in vitro. We have compared the ability of the cytochrome P-450 inhibitors cimetidine and metyrapone to enhance drug susceptibility with that of verapamil by using wild-type malaria isolates obtained from Cameroon. Verapamil completely reversed resistance, i.e., to below the cutoff point of 70 nM, in all the resistant isolates. Cimetidine enhanced chloroquine susceptibility in 60% of the isolates and reduced 50% inhibitory concentrations by at least 43% in all the resistant isolates. The compounds tested had little or no effect on the 50% inhibitory concentrations for the susceptible isolates. The data support a possible role for detoxification in chloroquine resistance, and even in the absence of such a process we have observed apparent chemosensitization by agents whose common biological feature is the inhibition of cytochrome P-450 enzymes. Additionally, sensitization has been observed in wild-type isolates of P. falciparum obtained form immune residents of an area of endemicity as well as culture-adapted parasites.
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PMID:Enhancement of drug susceptibility in Plasmodium falciparum in vitro and Plasmodium berghei in vivo by mixed-function oxidase inhibitors. 832 80


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