Effect of cimetidine on δ-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver

Marcus, David L.; Halbrecht, Jeffrey; Bourque, Anita L.; Lew, George; Nadel, Harriet; Freedman, Michael L.

doi:10.1016/0006-2952(84)90565-3

Cited by 33 publications

(21 citation statements)

References 29 publications

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“…Other studies have shown that cimetidine inhibits the enzymes involved in haem synthesis and 324 degradation (Marcus et al 1984). A major point of contention has been the observation by numerous investigators that, in vitro, the concentration of cimetidine required to inhibit xenobiotic metabolism is an order of magnitude higher than that obtained in patients being treated with cimetidine and for whom inhibition of drug metabolism could be demonstrated.…”

Section: The Cytochrome P-450 Mixed Functionmentioning

confidence: 98%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

183

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The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: The Cytochrome P-450 Mixed Functionmentioning

confidence: 98%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

183

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“…CIM also prevented ALA-S induction provoked by DAB restoring basal levels at the end of the treatment (A CIM ) and even partially reversed this induction in animals pre-treated with DAB (B CIM ), achieving a 43% diminution respect to the B S group (Figure 3a). CIM was found to inhibit both in vivo and in vitro the rate limiting enzymes of haem degradation, and it was suggested that the drug itself or a metabolite would inhibit HO (Marcus et al, 1984). In our experimental system, CIM given alone inhibited 25% HO activity and no effect was detected on the reduction of HO activity already provoked by DAB (Figure 3b).…”

Section: Resultsmentioning

confidence: 62%

Interaction of cimetidine with P450 in a mouse model of hepatocarcinogenesis initiation

et al. 2002

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Many drugs and xenobiotics are lipophilic and they should be transformed into more polar water soluble compounds to be excreted. Cimetidine inhibits cytochrome P450. The aim of this study was to investigate the preventive and/or reversal action of cimetidine on cytochrome P450 induction and other metabolic alterations provoked by the carcinogen pdimethylaminoazobenzene. A group of male CF1 mice received a standard laboratory diet and another group was placed on dietary p-dimethylaminoazobenzene (0.5% w w 71 ). After 40 days of treatment, animals of both groups received pdimethylaminoazobenzene and two weekly doses of cimetidine (120 mg kg 71 , i.p.) during a following period of 35 days. Cimetidine prevented and reversed d-aminolevulinate synthetase induction and cytochrome P450 enhancement provoked by p-dimethylaminoazobenzene. However, cimetidine did not restore haem oxygenase activity decreased by p-dimethylaminoazobenzene. Enhancement in glutathione S-transferase activity provoked by p-dimethylaminoazobenzene, persisted in those animals then treated with cimetidine. This drug did not modify either increased lipid peroxidation or diminution of the natural antioxidant defence system (inferred by catalase activity) induced by p-dimethylaminoazobenzene. In conclusion, although cimetidine treatment partially prevented and reversed cytochrome P450 induction, and alteration on haem metabolism provoked by p-dimethylaminoazobenzene AB, it did not reverse liver damage or lipid peroxidation. These results further support our hypothesis on the necessary existence of a multiple biochemical pathway disturbance for the onset of hepatocarcinogenesis initiation.

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“…In addition, through inhibiting cytochrome P450 mediated drug metabolism it reduces heme oxygenase activity. Heme consumption can be declined to reduce ALAS activity indirectly by negative feedback [10]. Horie et al reported that Cimetidine can be used to treat primary as well as recurrence AIP cases effectively.…”

Section: Discussionmentioning

confidence: 99%

Cimetidine in the Treatment of Acute Intermittent Porphyria from Onset to Death

Xie¹,

Yan²

2015

J Blood Disord Transfus

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Acute intermittent porphyria (AIP) is a rare, frequently misdiagnosed disease characterized by abdominal pain and psychiatric symptoms. Abdominal pain is the most common. At present, there is no radical cure for AIP. Hematin is considering the effective treatment to relieve the symptom. However, it is not available in china. A 25-year-old Chinese woman complained about intermittent abdominal pain for 2 years. He was misdiagnosed as acute abdominal disease many times. During attacks, abdominal pain relief always took more than 1 week without effective treatment. In our hospital, the patient was diagnosed AIP definitely and treated with intravenous cimetidine 400mg Q6h, symptoms especially abdomen pain relieved within 48-72 hours completely in each acute attack. Few cases of cimetidine to treat AIP have been reported. More clinical date is required in order to verify whether the routine treatment of cimetidine can replace hematin or be used as a preventive treatment. This is the first case to report that cimetidine has obvious effect during AIP acute attacks.

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Effect of cimetidine on δ-aminolevulinic acid synthase and microsomal heme oxygenase in rat liver

Cited by 33 publications

References 29 publications

Pharmacokinetic Interactions of Cimetidine 1987

Pharmacokinetic Interactions of Cimetidine 1987

Interaction of cimetidine with P450 in a mouse model of hepatocarcinogenesis initiation

Cimetidine in the Treatment of Acute Intermittent Porphyria from Onset to Death

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