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)

Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was metabolized to its reductive product, 2-sulfamoylacetylphenol, in rat liver microsomes under anaerobic conditions. The rate of NADPH-dependent reaction was much more rapid than that of NADH-dependent reaction. Furthermore, synergistic effect of NADH on NADPH-dependent reaction was not observed. The optimal formation of 2-sulfamoylacetylphenol from zonisamide in the presence of NADPH was observed around pH 7.0. Cimetidine showed an inhibitory effect on the formation of 2-sulfamoylacetylphenol in a dose-dependent manner. The reductive metabolism of zonisamide was almost completely inhibited by carbon monoxide, and was increased by pretreatment of rats with phenobarbital and pregnenolone 16 alpha-carbonitrile but not by pretreatment with ethanol, 3-methylcholanthrene and imidazole. These results suggest that phenobarbital- and pregnenolone 16 alpha-carbonitrile-inducible form(s) of cytochrome P-450 is responsible for the reductive metabolism of zonisamide to 2-sulfamoylacetylphenol in rat liver microsomes.
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PMID:Formation of reductive metabolite, 2-sulfamoylacetylphenol, from zonisamide in rat liver microsomes. 143 79

Both cimetidine and cyclosporine (CsA) are metabolized by the cytochrome P-450 system. Thus, coadministration of cimetidine and CsA may alter CsA metabolism. Because isoenzymes with the cytochrome P-450 system have variable drug-metabolizing effects, it is unclear whether a clinically significant drug-drug interaction will occur. We studied the acute effects of oral cimetidine administration on CsA metabolism in five orthotopic liver transplant patients and the chronic effects of oral cimetidine administration on CsA trough levels and liver and renal function in two. Cimetidine administration was associated with significantly higher CsA levels 60 and 120 min after an oral CsA dose (p = 0.004 and p = 0.002, respectively). Cimetidine had no effect on CsA levels drawn 240 and 480 min after the CsA dose or on trough levels. Cimetidine was found to have no effect on CsA trough levels when given over a 4-wk study period. Liver tests during the 4-wk period remained unchanged. Although there was a slight rise in serum creatinine, there was no change in blood urea nitrogen or renal clearance of [125I]iothalamate. We conclude that oral cimetidine administration significantly alters early CsA metabolism, but does not appreciably change CsA trough levels. Cimetidine appears safe to use in orthotopic liver transplant patients on CsA over at least a 4-wk period.
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PMID:The effect of cimetidine on cyclosporine A levels in liver transplant recipients: a preliminary report. 153 61

Cimetidine is considered to be a general inhibitor of cytochrome P-450 enzymes, but there is indirect evidence that certain cytochrome P-450 enzymes are not inhibited by cimetidine. The purpose of this study was to determine whether cimetidine, when administered in vivo to adult male Wistar rats, selectively inhibits hepatic microsomal cytochrome P-450 enzymes. Uninduced, phenobarbital (PB)-induced and dexamethasone (DEX)-induced rats were sacrificed 90 min after treatment with a single i.p. dose of cimetidine HCI (150 mg/kg) or saline. Hepatic microsomes were prepared, and aminopyrine N-demethylase (APND), pentoxyresorufin O-dealkylase (PROD), erythromycin N-demethylase (EMND) activities and oxidation of testosterone were determined. In addition, immunoinhibition studies with a polyclonal antibody monospecific for cytochrome P-450IIC11 were performed. Cimetidine treatment inhibited APND, PROD and EMND activities to a greater extent in microsomes from uninduced rats than in those from PB- or DEX-induced rats, suggesting that the induced cytochrome P-450 enzymes were less affected by cimetidine than were those in uninduced rats. Cimetidine treatment inhibited testosterone 2 alpha-hydroxylase activity by 65, 73 and 46%, respectively, in microsomes from uninduced, PB-induced and DEX-induced rats. The antibody completely inhibited testosterone 2 alpha-hydroxylase activity in the three groups of microsomes, indicating that this activity is specific for cytochrome P-450IIC11 in all these cases. Neither cimetidine treatment nor the antibody inhibited microsomal testosterone 2 beta-, 6 beta-, 7 alpha- or 16 beta-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective inhibition of rat hepatic microsomal cytochrome P-450. I. Effect of the in vivo administration of cimetidine. 154 3

The purpose of this study was to determine whether the differential inhibition of rat hepatic microsomal cytochrome P-450 in adult male rats by in vivo cimetidine administration is observed when the drug is administered in vitro. Cimetidine, at concentrations of up to 10 mM, did not affect the catalytic function of cytochrome P-450IIA1 as measured by testosterone 7 alpha-hydroxylase activity. In contrast, it did inhibit activities that are specific for cytochromes P-450IIC11 (testosterone 2 alpha-hydroxylase activity), P-450IIB1/2 (testosterone 16 beta-hydroxylase activity) and P-450IIA1/2 (testosterone 2 beta- and 6 beta-hydroxylase activities), with IC50 values in the range of 1.0 to 7.4 mM. To further investigate the inhibition of cytochrome P-450 enzymes by in vitro cimetidine, preincubation experiments were performed. Hepatic microsomes were preincubated with a low concentration (0.05 mM) of cimetidine and 1 mM NADPH for 15 min before the initiation of substrate (testosterone) oxidation. Under these conditions, cimetidine resulted in the inhibition of the enzyme activities specific for cytochrome P-450IIC11, but it had no effect on those specific for cytochromes P-450IIA1, P-450IIB1/2 and P-450IIIA1/2. This differential inhibition by in vitro cimetidine required the presence of NADPH in the preincubation medium, suggesting that a catalysis-dependent process is involved. Therefore, preincubation of hepatic microsomes with NADPH and a relatively low concentration (0.05 mM) of cimetidine in vitro results in a pattern of inhibition of cytochrome P-450 enzymes similar to that which occurs after the in vivo administration of cimetidine reported in the previous study (Chang et al., 1992).
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PMID:Selective inhibition of rat hepatic microsomal cytochrome P-450. II. Effect of the in vitro administration of cimetidine. 154 4

The elimination of the antiviral drug 5-ethyl-2'-deoxyuridine (EdUrd) by the isolated perfused rat liver was investigated. EdUrd (3.9-39 mumol) was injected into the perfusion reservoir and serial samples were collected for HPLC determination of EdUrd and its metabolites 5-ethyluracil (EUra) and 5-(1-hydroxyethyl)uracil (HEUra). At each dosage level, semilogarithmic plots of concentration vs. time showed apparent first order disappearance of EdUrd. However, with increasing dose, there was a progressive increase in EdUrd half-life from 18.9 to 36.4 min and decrease in total clearance from 5.5 to 2.5 ml/min, indicating dose-dependent elimination. Dose dependence was confirmed by the lack of superposition of logarithm concentration/dose vs. time plots obtained with different doses. After EdUrd administration, the concentration of EUra reached a peak value in about 1 hr, and then gradually decreased. The concentration of HEUra, which was initially much lower than that of EUra, increased throughout the experiment and appeared to approach a plateau at 2-3 hr. Biliary excretion of each ethylpyrimidine was negligible. 6-Benzyl-2-thiouracil, a thymidine phosphorylase inhibitor, slowed the disappearance of EdUrd and decreased the peak concentrations of EUra and HEUra. Cimetidine, a cytochrome P-450 inhibitor, had little effect on the rate of EdUrd disappearance, but caused a large increase in the peak EUra concentration and decrease in HeUra concentration. 3-Methylcholanthrene, a cytochrome P-450 inducer, increased the formation of HEUra but had little effect on the rate of EdUrd disappearance. The results indicate that the hepatic elimination of EdUrd is dose-dependent and involves an initial cleavage to EUra, which is then oxidized to HEUra.
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PMID:Elimination of the antiviral drug 5-ethyl-2'-deoxyuridine by the isolated perfused rat liver. 168 11

Treatment of newborn lambs with the cytochrome P-450 (P-450) inhibitor cimetidine and treatment of adult rats with P-450 inducer 3-methylcholanthrene have been reported to provide protection against oxygen-induced lung damage. Cimetidine (30 or 100 mg/kg/day) and 3-methylcholanthrene (25 mg/kg on days 1 and 2) were tested for their ability to protect newborn rats from the acute and chronic lung disease that follows exposure to 100% oxygen. Half of the rats in each group was exposed to 100% oxygen for 8 days; the other half was maintained in room air. Pulmonary microsomes from 1- to 8-day-old rats contained low levels of total cytochrome P-450 and P-450 IIB1, but undetectable levels of P-450 IA1. Exposure to 100% oxygen and/or treatment with cimetidine had no significant effect on P-450 levels, whereas treatment with 3-methylcholanthrene markedly induced IA1. Survival in 100% oxygen was not affected by cimetidine treatment, but was significantly decreased by 3-methylcholanthrene treatment. At 60 days of age, those rats that survived neonatal exposure to 100% oxygen had elevated right ventricular systolic pressure, increased muscularization of arterioles, and enlarged and irregular alveoli, regardless of the neonatal treatment. These results indicate that 3-methylcholanthrene potentiated the toxic effects of oxygen in newborn rats, in contrast to the protective effect reported for adult rats, whereas cimetidine had no discernable effect on oxygen-induced lung toxicity, in contrast to the protective effect reported for newborn lambs. The induction of cytochrome P-450 IA1 by 3-methylcholanthrene may be important in potentiating the toxic effects of oxygen in the neonatal rat lung.
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PMID:Oxygen-induced lung damage in newborn rats, potentiated by 3-methylcholanthrene, a P-450 inducer, and lack of protection by cimetidine, a P-450 inhibitor. 192 Jan 30

Cimetidine binds to cytochrome P-450 and inhibits hepatic metabolism of various drugs in humans. However, cytochrome P-450 is a family of enzymes rather than a single protein, and effects of cimetidine on individual human liver cytochromes P-450 have not been previously characterized. Metabolism of selected substrates and cimetidine-binding assays have been performed using human liver microsomes, purified human liver cytochromes P-450, and cytochrome P-450 complementary DNA-expressed yeast proteins to probe interaction of cimetidine with these individual enzymes. Cimetidine (3.0 mmol/L) in incubations reduced bufuralol hydroxylase activity by 80% and strongly inhibited microsomal nifedipine oxidation (23% +/- 13% of control activity). The same concentration of cimetidine produced intermediate inhibition of cytochrome enzymes responsible for ethoxyresorufin deethylation and aniline hydroxylation (77% +/- 6% and 68% +/- 17% of activity in control microsomal incubations, respectively), but little effect on tolbutamide hydroxylation was observed. Concordantly, the calculated binding constant for the binding of cimetidine to a purified cytochrome P-450 with high tolbutamide hydroxylase activity was 4.4 mmol/L, whereas the calculated binding concentration constant for a purified cytochrome P-450-metabolizing nifedipine was 0.7 mmol/L. These studies show a high variability in the effect of cimetidine on drug metabolism by individual human liver cytochromes P-450. In vitro studies using human liver microsomes and genetically engineered human cytochromes P-450 can be very useful in exploring important clinical questions of hepatic drug metabolism.
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PMID:Differential inhibition of individual human liver cytochromes P-450 by cimetidine. 195 33

Cimetidine may decrease concomitant medication clearance by inhibiting the oxidative system of cytochrome P-450. The authors report increased serum clozapine levels and adverse side effects during clozapine and cimetidine treatment but not during clozapine and ranitidine treatment in a patient with chronic paranoid schizophrenia.
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PMID:A case report of cimetidine-induced clozapine toxicity. 198 13

1. Cimetidine pretreatment of male Sprague-Dawley rats caused a significant increase in the specific content of total hepatic cytochrome P-450, supporting the hypothesis that this H2-receptor antagonist has monooxygenase induction effects. 2. Quantitative ultrastructural studies of liver of cimetidine-pretreated animals also supported this hypothesis in showing a significant proliferation of smooth endoplasmic reticulum. These ultrastructural changes were qualitatively similar to those produced by treatment of rats with phenobarbital, a well-characterized monooxygenase-inducing agent whose effects were studied for comparative purposes. 3. Competitive inhibition of metoprolol alpha-hydroxylation by cimetidine in liver microsomes prepared from untreated animals (Ki = 18.8 microM) was also demonstrated. 4. These results allowed testing of the hypothesis (Burnet et al. 1986) that inhibition of a defined monooxygenase should lead to induction of the synthesis of the relevant cytochrome P-450 isozyme. 5. The finding that metoprolol alpha-hydroxylase activity of liver microsomes was lowered, not elevated, by pretreatment of animals with cimetidine argues against the concept of a causal link between monooxygenase inhibition and induction.
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PMID:Cimetidine: an inhibitor and an inducer of rat liver microsomal cytochrome P-450. 205 75

H2-antagonists such as cimetidine and ranitidine are metabolized by cytochrome P-450. In this way they may interfere with theophylline metabolism. Cimetidine is known to have this effect and frequently to induce a theophylline toxic effect, while data concerning ranitidine are more uncertain. In this paper, we report the case of a 67-year-old woman with non-insulin dependent diabetes. She was taking aminophylline for respiratory failure and after ranitidine infusion exhibited generalized convulsions. Theophylline values which were monitored within the therapeutic range, increased toxic levels after ranitidine therapy and epileptic episodes. The increase in theophylline levels was associated with a further reduction in the clearance rate of the bronchodilator. We think that ranitidine may combine with other clinical factors known to reduce theophylline metabolism mainly in the elderly and severely ill patients. Theophylline-induced seizures may occur when theophylline serum levels are slightly above the therapeutic range, as in our case report.
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PMID:Seizures during concomitant treatment with theophylline and ranitidine: a case report. 209 63


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