The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin*

Sarich, Troy C.; Kalhorn, Thomas F.; Magee, Sara; Alsayegh, Faisal; Adams, Stephen P.; Slattery, John T.; Goldstein, Joyce A.; Nelson, Sidney D.; Wright, James M

doi:10.1016/s0009-9236(97)90148-x

Cited by 58 publications

(38 citation statements)

References 30 publications

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“…2,3) It has been generally accepted that the role of CYP1A2 and 3A4 in generation of NAPQI is very small compared with that of CYP2E1. 3,33,34) In this study a dose of DMSO to mice decreased the microsomal CYP1A2 and 3A activities determined with aminopyrine and erythromycin as substrates. The contribution of inhibition of CYP1A2 and/or 3A activities by DMSO to the reduction of generation of a reactive metabolite from APAP in vivo is not known.…”

Section: Effect Of Dmso On Apap-induced Toxicity In Micementioning

confidence: 55%

Effects of Dimethylsulfoxide on Metabolism and Toxicity of Acetaminophen in Mice

Yoon

Kim

Lee

et al. 2006

Biological & Pharmaceutical Bulletin

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Dimethylsulfoxide (DMSO) is frequently used as a solvent in various in vivo and in vitro experiments. The use of this solvent is favored especially when physicochemical properties of a test compound have not been well characterized such as in the case of natural products. But DMSO is not biologically inert. DMSO has numerous pharmacological effects, the most well-known of which is hydroxyl radical scavenging capacity. Therefore, it is suspected that toxicological implications of the interaction of DMSO with a xenobiotic, either directly or indirectly via body system, would be complex.Acetaminophen (APAP), a widely used analgesic-antipyretic, is detoxified rapidly through formation of sulfate and glucuronide conjugates. 1) However, at large doses this drug is increasingly converted into a reactive metabolite, Nacetyl-p-benzoquinonimine (NAPQI). The metabolic activation of APAP in human is mediated by CYP2E1, 1A2 and 3A4.2,3) The relative contribution of each CYP isozyme to formation of the toxic metabolite is not clear, however, it has been generally accepted that CYP2E1 has the principal role in metabolic activation of this drug both in human and rodents. The reactive metabolite is normally detoxified by conjugation with glutathione (GSH), subsequently resulting in generation of APAP-mercapturate via APAP-cysteine. When generation of the reactive metabolite exceeds the availability of GSH for conjugation reaction, covalent binding of the metabolite to macromolecules may result, an event that correlates with induction of hepatic necrosis.4) Therefore, the most important determinants for induction of APAP toxicity are the metabolic activities catalyzing its activation and the effectiveness of GSH conjugation reaction.It has been shown that induction of APAP hepatotoxicity may be decreased by a dose of DMSO in mice 5) and also in hamsters. 6) In mice DMSO was found to decrease covalent binding of APAP metabolites to hepatic protein, but the microsomal aniline hydroxylase activity was rather increased. 7)Accordingly, the authors suggested that the protective effect of DMSO was due to interaction of DMSO with free radicals or reactive APAP metabolites. Later studies revealed that the protection provided by DMSO was tissue-specific, which would exclude the possibility of involvement of a nonspecific mechanism such as scavenging of free radicals. 8) Also DMSO was shown to inhibit the biliary concentration of APAP-GSH and the microsomal dimethylnitrosamine Ndemethylase activity. 9) Therefore, it appears that the protective effect of DMSO against APAP liver toxicity is associated with inhibition of CYP-dependent activation of this drug. Meanwhile, conflicting results were demonstrated in studies examining the effects of DMSO on metabolism and toxicity of other xenobiotics that are also metabolically activated by CYP2E1. For instance, DMSO was shown to enhance the hepatotoxicity of carbon tetrachloride (CCl 4 ), 10) while other studies demonstrated reduction of CCl 4 -induced hepatotoxicity in rats and mice. 11,12) Differ...

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Section: Effect Of Dmso On Apap-induced Toxicity In Micementioning

confidence: 55%

Effects of Dimethylsulfoxide on Metabolism and Toxicity of Acetaminophen in Mice

Yoon

Kim

Lee

et al. 2006

Biological & Pharmaceutical Bulletin

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“…Consistent with the findings in mice, induction of human CYP1A2 seems to have little effect on the formation of the reactive metabolite NAPQI of acetaminophen. In a clinical study with EMs and PMs of CYP2C19, omeprazole was administered orally at 40 mg daily for 7 days (226). A significant CYP1A2 induction was observed only in the PMs, but not in EMs of CYP2C19.…”

Section: Induction In Toxicitymentioning

confidence: 99%

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

2006

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Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed.

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“…Recent pharmacokinetic studies in human volunteers have demonstrated that the involvement of CYP1A2 and CYP3A4 in NAPQI formation in vivo is much less than that of CYP2E1 (Sarich et al, 1997;Manyike et al, 2000). Additionally, studies using CYP2E1 and CYP1A2 knockout mice have shown that the former, but not the latter, are more resistant to APAP-induced hepatotoxicity than are wild-type animals (Lee et al, 1996;Tonge et al, 1998;Zaher et al, 1998), indicating that among the CYPs CYP2E1 is a primary contributor to APAP biotransformation.…”

Section: Effect Of Gga On Cyp2e1 Activity and Hepatic Gsh Depletionmentioning

confidence: 99%

Geranylgeranylacetone protects against acetaminophen-induced hepatotoxicity by inducing heat shock protein 70

et al. 2006

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The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin*

Cited by 58 publications

References 30 publications

Effects of Dimethylsulfoxide on Metabolism and Toxicity of Acetaminophen in Mice

Effects of Dimethylsulfoxide on Metabolism and Toxicity of Acetaminophen in Mice

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

Geranylgeranylacetone protects against acetaminophen-induced hepatotoxicity by inducing heat shock protein 70

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