Inhibition of drug metabolism in human liver microsomes by nizatidine, cimetidine and omeprazole

Furuta, Shigeru; Kamada, Emiko; Suzuki, Takashi; Sugimoto, Tohru; Kawabata, Yoshihiro; Shinozaki, Yutaka; Sano, Hiroshi

doi:10.1080/00498250110035615

Cited by 53 publications

(35 citation statements)

References 18 publications

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“…The present study has shown that cimetidine is a weak, reversible inhibitor of CYP2D6 in vitro, a finding consistent with reports from other laboratories (Martinez et al, 1999;Furuta et al, 2001). Additionally, evidence presented here suggests that cimetidine acts as a mechanism-based inactivator of CYP2D6.…”

Section: Discussionsupporting

confidence: 82%

“…Cimetidine also appears to inhibit the metabolism of debrisoquine (Philip et al, 1989) and dextromethorphan (Arnold et al, 1997), but clearance values were not obtained in these studies. Inhibition of CYP2D6 has also been investigated in vitro, and studies have demonstrated that cimetidine competitively inhibits bufuralol hydroxylase activity with a K i of 50 to 55 M (Knodell et al, 1991;Furuta et al, 2001). However, this value is approximately 5-fold greater than the maximal plasma level of cimetidine of 10 M achieved during normal therapy (Brogden et al, 1978).…”

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confidence: 99%

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THE EFFECT OF CIMETIDINE ON DEXTROMETHORPHAN O-DEMETHYLASE ACTIVITY OF HUMAN LIVER MICROSOMES AND RECOMBINANT CYP2D6

Madeira

Levine²,

Chang³

et al. 2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Clinically, cimetidine therapy impairs the clearance of various drugs metabolized by CYP2D6, such as desipramine and sparteine. Cimetidine is known to reversibly inhibit CYP2D6 in vitro; however, K i values are greater than plasma concentrations observed in vivo. There is evidence suggesting that this drug may act as an inactivator of cytochrome P450 (P450) enzymes after metabolic activation. Therefore, the purpose of this study was to determine whether cimetidine acts as a mechanism-based inactivator of CYP2D6. Dextromethorphan O-demethylation was used as a probe of CYP2D6 activity. The V max and K m of this reaction were 0.82 ؎ 0.06 nmol/min/nmol of P450 and 4.1 ؎ 0.1 M, respectively, in pooled human liver microsomes; and 15.9 ؎ 0.8 nmol/min/nmol P450 and 1.4 ؎ 0.6 M, respectively, with recombinant CYP2D6.With human liver microsomes, cimetidine competitively inhibited CYP2D6 (K i ‫؍‬ 38 ؎ 5 M) and was a mixed inhibitor of recombinant CYP2D6 (K i ‫؍‬ 103 ؎ 17 M). Preincubation of human liver microsomes with cimetidine and NADPH did not increase the inhibitory potency of cimetidine; however, preincubation with recombinant CYP2D6 resulted in enzyme inactivation that could be attenuated by the CYP2D6 inhibitor quinidine. The K I and k inact were estimated to be 77 M and 0.03 min ؊1 , respectively, and the half-life of inactivation was 25 min. Therefore, cimetidine may represent a class of compounds capable of inactivating specific cytochromes P450 in vivo, but for which conditions may not be achievable in vitro using human liver microsomes.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

THE EFFECT OF CIMETIDINE ON DEXTROMETHORPHAN O-DEMETHYLASE ACTIVITY OF HUMAN LIVER MICROSOMES AND RECOMBINANT CYP2D6

Madeira

Levine²,

Chang³

et al. 2004

Drug Metab Dispos

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“…The properties of CYP inhibitors toward human liver microsomes have been extensively characterized, and selective inhibitors for some isozymes have been identified. The only human isozyme that is inhibited by chloramphenicol, cimetidine, and sulfaphenazole is CYP2C9 (15,(18)(19)(20)(21). Considering that a CYP2C9-like activity has been demonstrated in rat arteries, it is reasonable to hypothesize that inhibition of this enzyme is the basis of protection by chloramphenicol, cimetidine, and sulfaphenazole.…”

Section: Discussionmentioning

confidence: 99%

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Granville

Tashakkor²,

Takeuchi³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

157

113

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Ischemia and reperfusion both contribute to tissue damage after myocardial infarction. Although many drugs have been shown to reduce infarct size when administered before ischemia, few have been shown to be effective when administered at reperfusion. Moreover, although it is generally accepted that a burst of reactive oxygen species (ROS) occurs at the onset of reperfusion and contributes to tissue damage, the source of ROS and the mechanism of injury is unclear. We now report the finding that chloramphenicol administered at reperfusion reduced infarct size by 60% in a Langendorff isolated perfused rat heart model, and that ROS production was also substantially reduced. Chloramphenicol is an inhibitor of mitochondrial protein synthesis and is also an inhibitor of a subset of cytochrome P450 monooxygenases (CYPs). We could not detect any effect on mitochondrial encoded proteins or mitochondrial respiration in chloramphenicol-perfused hearts, and hypothesized that the effect was caused by inhibition of CYPs. We tested additional CYP inhibitors and found that cimetidine and sulfaphenazole, two CYP inhibitors that have no effect on mitochondrial protein synthesis, were also able to reduce creatine kinase release and infarct size in the Langendorff model. We also showed that chloramphenicol reduced infarct size in an open chest rabbit model of regional ischemia. Taken together, these findings implicate CYPs in myocardial ischemia͞reperfusion injury.C urrent treatment of myocardial infarction is directed at the restoration of blood flow to the ischemic region and reduction of myocardial oxygen demand. However, during reperfusion, the heart undergoes further damage due, in large part, to the generation of reactive oxygen species (ROS) (1). It is clear that permanent ischemia results in necrotic cell death. However, it is unclear whether reperfusion itself induces apoptosis or merely permits the manifestation of cell death processes that were initiated and irreversibly committed to during ischemia. Moreover, the relative contributions to tissue injury by the ischemic phase and by reperfusion have been difficult to evaluate. Resolving this question carries important therapeutic implications, as efforts directed toward treating reperfusion injury would have limited value if most cell death were predestined during ischemia.Although we initially hypothesized that the protective effect of chloramphenicol was caused by inhibition of mitochondrial protein synthesis, we did not see down-regulation of mitochondrial-encoded proteins after chloramphenicol infusion. The energy-sparing effects of inhibition of cytosolic protein synthesis have been described (2), and our previously reported observation that mitochondrial elongation factor Tu is phosphorylated during ischemia suggests a similar process may take place in the mitochondria (3). However, because chloramphenicol also inhibits some cytochrome P450 monooxygenases (CYPs), it was important to determine whether that inhibitory effect was relevant to cardioprotection. In this re...

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“…It was also proposed, that the varying effects of CIM on P450 enzymes could be attributed to different CIM binding affinities for these mixed function oxidases (Faux and Combes, 1993). The inhibitory effect of CIM on the metabolic activity of CYP2C9, 2C19, 2D6 y 3A was recently demonstrated in human liver microsomes (Furuta et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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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Inhibition of drug metabolism in human liver microsomes by nizatidine, cimetidine and omeprazole

Cited by 53 publications

References 18 publications

THE EFFECT OF CIMETIDINE ON DEXTROMETHORPHAN O-DEMETHYLASE ACTIVITY OF HUMAN LIVER MICROSOMES AND RECOMBINANT CYP2D6

THE EFFECT OF CIMETIDINE ON DEXTROMETHORPHAN O-DEMETHYLASE ACTIVITY OF HUMAN LIVER MICROSOMES AND RECOMBINANT CYP2D6

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

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

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