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)

Cimetidine, the first marketed histamine2-receptor antagonist, has been shown to decrease the clearance of warfarin consistently through inhibition of cytochrome P-450 metabolism. The clinical significance of this drug-drug interaction has been questioned due to: (1) the lowering of the warfarin therapeutic range, (2) the lowering of the total daily therapeutic cimetidine dosage, (3) the advent of once-daily cimetidine dosing, and (4) the demonstration that the clearance of the less active warfarin R-enantiomer is decreased to a greater extent than the more active S-enantiomer. Ranitidine has been implicated in both increasing and decreasing warfarin's hypoprothrombinemic-effect (noted in the warfarin package insert), despite the majority of investigations demonstrating no warfarin clearance changes. Careful examination of the implicating data indicates that the majority of the warfarin pharmacodynamic and pharmacokinetic variance that occurs with combined ranitidine-warfarin therapy cannot be attributed to a drug-drug interaction. No data are available to implicate the newer histamine2-antagonists, famotidine and nizatidine, in causing a decrease in warfarin metabolism.
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PMID:Do all histamine2-antagonists cause a warfarin drug interaction? 257 90

The effects of cimetidine (CIM) (an inhibitor of the hepatic microsomal monooxygenase system) on the metabolism and hepatotoxicity of trichloroethylene (TRI) were studied in male Sprague-Dawley rats. Rats were given three doses of 120 mg/kg i.p. (low-dose regimen) of CIM at 0, 6 and 11 h for 1 day, or ten doses of 200 mg/kg (high-dose regimen) at 8, 11, 14 and 17 h for 2 days and 8 and 11 h on 3rd day. Trichloroethylene (0.5 or 0.65 ml/kg) was administered i.p. 1 h after 2nd dose (low-dose regimen) or 9th dose (high-dose regimen) of CIM. In the low-dose regimen study, the activity of hepatic microsomal aminopyrine N-demethylase was decreased 1 and 5 h after the second dose and 7 h after the third dose of CIM, but became normal 20 h after the last dose. The cytochrome P-450 content and the activities of aniline hydroxylase and epoxide hydratase remained unchanged. Trichloroethylene at both dose levels produced liver toxicity, as verified by increase in activities of SDH and SGPT as well as by liver histology. Cimetidine alone had no such effect. An apparent reduction in TRI toxicity by CIM (at both dose regimens) could be observed histologically. The biochemical tests (SDH and SGPT) corroborated the histological changes only when TRI was given at a dose of 0.5 ml/kg combined with a high-dose regimen of CIM. Cimetidine at both dose regimens had a tendency to decrease the in vivo metabolism of TRI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of cimetidine on hepatic biochemical changes, liver toxicity and major urinary metabolite excretion of trichloroethylene in rats. 271 69

Cimetidine, a histamine H2-receptor antagonist widely used to treat peptic ulceration, is known to cause gynecomastia and sexual dysfunction in some men. Since cimetidine inhibits the cytochrome P-450-dependent biotransformation of numerous drugs, we investigated the possibility that it might also inhibit the cytochrome P-450--dependent metabolism of estradiol. Radiometric analysis of urine and serum samples from nine normal male volunteers showed that the extent of 2-hydroxylation of estradiol was significantly reduced from a mean (+/- SEM) of 31.7 +/- 2.3 percent to 19.7 +/- 2.3 percent (P less than 0.0001) after two weeks of oral treatment with cimetidine (800 mg twice a day); the 16 alpha-hydroxylation of estradiol was unaffected. At the same time, the urinary excretion of 2-hydroxyestrone decreased by approximately 25 percent (P less than 0.0002), and the serum concentration of estradiol increased by approximately 20 percent (P less than 0.04). The mean percentage of estradiol 2-hydroxylation was also rapidly reduced, from 36.8 +/- 4.4 percent to 24.5 +/- 3.4 percent in six men after one week of oral cimetidine at a lower dosage (400 mg twice a day; P less than 0.0006). In a separate study of seven men, ranitidine, a second-generation H2-receptor antagonist, was found to have no effect on the 2-hydroxylation of estradiol. This study demonstrates that the administration of cimetidine to men decreases the 2-hydroxylation of estradiol and results in an increase in the serum estradiol concentration. This mechanism may help to account for the signs and symptoms of estrogen excess reported with the long-term use of cimetidine.
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PMID:The effects of cimetidine on the oxidative metabolism of estradiol. 274 69

Cimetidine, a substituted imidazole, is an inhibitor of hepatic cytochrome P-450-mediated drug metabolism in rats and humans. We investigated the effect of cimetidine on phenobarbital induction of hepatic microsomal aminopyrine N-demethylase activity in the rat. Phenobarbital induction of aminopyrine N-demethylase was log-linear in the range of 1-6 mg/kg/day and the ED50 was approximately 3 mg/kg/day. Cimetidine 75 mg/kg (four times a day) attenuated the induction of aminopyrine N-demethylase activity by 58% in low dose (3 mg/kg/day) but not in high dose (40 mg/kg/day) phenobarbital treated rats. This result could not be explained by residual inhibition of enzyme activity by cimetidine and suggests that cimetidine affects the induction of hepatic cytochrome P-450 by low dose phenobarbital.
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PMID:Attenuation of low dose phenobarbital induction of hepatic microsomal aminopyrine N-demethylase activity in rats by cimetidine. 276 37

The effects of nizatidine (a new H2-receptor antagonist) and of related compounds were studied on oxidative drug metabolism in the rat both in vivo and in vitro. Nizatidine is a structural analog of the H2-receptor antagonists ICI 125,211 (Tiotidine) and ranitidine (Zantac). Nizatidine (120 mg/kg, ip) had no effect on the [14C]aminopyrine (ABT) or [14C]caffeine breath (CBT) tests, nor on the clearance from plasma of aminopyrine despite high tissue and plasma concentrations of nizatidine. Binding of nizatidine (1 mM) to rat hepatic microsomal P-450 determined by spectral analysis was not observed. In vitro aminopyrine demethylation was inhibited by nizatidine only at high concentrations (Ki = 92 mM). Cimetidine, ICI 125,211, and imidazole bind avidly to rat hepatic microsomal cytochrome P-450 and are potent inhibitors of aminopyrine demethylation in vitro. Imidazole inhibited the aminopyrine breath test, while imidazole, ranitidine, and ICI 125,211 inhibited the caffeine breath in vivo. These data indicate that nizatidine has no acute inhibitory effect on hepatic oxidative drug metabolism in the rat, both in vitro and in vivo. The composite structural-activity data suggest that inhibition of in vivo oxidative drug metabolism by H2-antagonists may not depend primarily on either the imidazole ring side chain or the thiazole ring per se. Furthermore, the in vivo inhibition may not correlate with in vitro data.
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PMID:Nizatidine, a new histamine H2-receptor antagonist, and hepatic oxidative drug metabolism in the rat: a comparison with structurally related compounds. 285 33

The metabolism of metyrapone was investigated in three mammalian and four non-mammalian species, and keto reduction was found to be the major metabolic route (except in the cat). Toad, lizard and tortoise did not form metyrapone N-oxides. Rat and cat formed both isomeric N-oxides of metyrapone, whereas rabbit and pigeon have a limited capacity to form only the N-oxide II and N-oxide I, respectively. There were marked sex differences in both keto reduction and N-oxidation in the rat. Anthracene did not affect metyrapone N-oxides formation in the male rat; however phenobarbitone and pregnenolone significantly induced N-oxide II formation, whereas ethanol induced both isomeric N-oxides formation. Cimetidine, a known cytochrome P-450 inhibitor, inhibited the N-oxide II formation but with an enhanced N-oxide I formation.
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PMID:Influence of species, sex and drug pretreatment on the metabolism of metyrapone. 286 Oct 55

Theobromine metabolism and clearance were investigated at steady-state under chronic oral dosing conditions in eight healthy volunteers, four of whom were cigarette smokers. The subjects were studied before and after separate 1 week pretreatments with cimetidine (1 g/day) and sulfinpyrazone (800 mg/day). Theobromine plasma clearance (ClTB) was 33% higher in smokers than in non-smokers due to induction of all metabolic pathways (3-demethylation, 7-demethylation, and formation of 6-amino-5-(N-methylformylamino)-1-methyluracil (AMMU]. 7-Demethylation was induced by cigarette smoking to a greater extent than the other pathways. Cimetidine pretreatment inhibited theobromine 3-demethylation and AMMU formation resulting in a 27% decrease in ClTB in the combined smoker/nonsmoker group. The 7-demethylation pathway was unaffected by cimetidine. In contrast, sulfinpyrazone pretreatment increased ClTB by 50% in the whole group by approximately equal induction of each metabolic pathway. The extent of induction due to sulfinpyrazone was 2.4-fold greater in nonsmokers than in smokers. When compared with previous data relating to theophylline, the results suggest that theobromine 3-demethylation is mediated by the same form(s) of cytochrome P-450 involved in theophylline demethylation, while a second form(s) of cytochrome P-450 is involved in theobromine 7-demethylation and theophylline 8-hydroxylation. In addition, since AMMU formation was inhibited by cimetidine and induced by cigarette smoking and sulfinpyrazone, it would appear that the conversion of theobromine to AMMU is also mediated by cytochrome P-450.
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PMID:Influence of cimetidine, sulfinpyrazone, and cigarette smoking on theobromine metabolism in man. 286 10

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.
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PMID:Comparative effects of H2-receptor antagonists on drug interaction in rats. 287 21

It has been increasingly recognized that the histamine (H2)-receptor antagonists are associated in rare instances with idiosyncratic hepatotoxic reactions and with drug interactions related to their inhibition of the hepatic cytochrome P-450 enzymes. What have not been appreciated until recently are the potential therapeutic benefits that may be derived from cytochrome P-450 inhibition. Evidence is presented here that cytochrome P-450 inhibition may protect against hepatic damage induced by acetaminophen and other drugs metabolized via this system. Acetaminophen hepatotoxicity is an especially important problem because of the widespread use of this agent and the evidence that the potential for such injury may be increased in alcoholic persons. Cimetidine has been used in selected cases, one of which is described here, to treat acetaminophen hepatotoxicity. All H2-receptor antagonists may not be alike in this regard. Experimental studies in animal models indicate that although cimetidine protects against the hepatotoxic effects of acetaminophen, ranitidine may actually potentiate hepatic damage. It is thought that the difference between these two H2-receptor antagonists may lie in their affinities for binding to the cytochrome P-450 enzymes. Cimetidine, which binds more strongly, inhibits this system more efficiently, whereas the inhibition produced by ranitidine is not sufficient to confer a protective effect against drug-induced hepatotoxicity.
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PMID:Hepatotoxic and hepatoprotective potential of histamine (H2)-receptor antagonists. 289 10

The two imidazole histamine H2-receptor antagonists etintidine and cimetidine interact with the rat liver microsomal cytochrome P-450. From type II spectral changes follows that the affinity of rat liver microsomal preparations for etintidine is about 5 times as high as for cimetidine when comparing both high and low affinity binding sites. After pretreatment with phenobarbital etintidine inhibited benzphetamine N-demethylation competitively (app. Ki: 4.0 mmol/l). Cimetidine inhibited benzphetamine N-demethylation in the same range. After pretreatment with phenobarbital both drugs inhibited the oxidation of benzo(a)pyrene for which etintidine showed a higher inhibitory potency than cimetidine. However, this oxidation could not be inhibited when microsomes of 5,6-benzoflavone pretreated rats were used. After pretreatment with 5,6-benzoflavone only etintidine but not cimetidine inhibited the O-deethylation of ethoxyresorufin competitively (app. Ki: 0.2 mmol/l). Etintidine and cimetidine were metabolized by rat liver microsomes to their corresponding sulphoxides. In conclusion, etintidine may cause mainly the same drug interactions as cimetidine but seems to be a more potent inhibitor.
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PMID:Interactions of the histamine H2-receptor antagonist etintidine with rat liver cytochrome P-450: a comparison with cimetidine. 289 98


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