Cytochrome P450 mediated metabolism of diazepam in human and rat: involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner

Yasumori, Toshio; Nagata, Kiyoshi; Yang, Shen K.; Chen, Laishun; Murayama, Norie; Yamazoe, Yasushi; Kato, Ryuichi

doi:10.1097/00008571-199312000-00003

Cited by 97 publications

(40 citation statements)

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“…Sedative effect by diazepam infusion CYP2C19 genotype groups, several possible mechanisms can be raised as follows: first, the acute tolerance to diazepam may be developed, which is mediated by the dysfunction of the cortical GABA transmitter system, such as the decrease of glutaminic acid decarboxylase [31,32] , reelin [33] and GABA membrane transporter [34] , GABAA receptor up-regulation [35] and the decrease of dendritic spines [36] . Second, diazepam as well as its metabolites such as temazepam and N-desmethyldiazepam, have sedative effects [3,4] . Therefore, although the metabolic disposition of diazepam differs among the different CYP2C19 genotype groups, the total amounts of diazepam plus its active metabolites would not differ among the different CYP2C19 genotype groups, resulting in no statistical difference in the pharmacodynamics of diazepam.…”

Section: Discussionmentioning

confidence: 99%

“…Diazepam is metabolized by cytochrome P450 (CYP) 3A4 to temazepam, and by CYP3A4 and CYP2C19 to N-desmethyldiazepam [3,4] . There are genetic differences in the activity of CYP2C19 [3,4] .…”

Section: Introductionmentioning

confidence: 99%

“…There are genetic differences in the activity of CYP2C19 [3,4] . The pharmacokinetics of diaze pam significantly de pend on CYP2C19 genotype status [5][6][7][8][9] , as obser ved in proton pump inhibitors, such as omeprazole and rabeprazole [10,11] .…”

Section: Introductionmentioning

confidence: 99%

“…The CYP2C19 genotypes are classified into the three groups: homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) [12][13][14] . In PMs, the plasma diazepam concentrations are markedly increased due to an impaired metabolism of diazepam in comparison with those in EMs [3][4][5][6][7] . However, whether the pharmacodynamic effects of an intravenous infusion of diazepam would differ between the CYP2C19 EMs and PMs remain, to our knowledge, unknown.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Maintenance time of sedative effects after an intravenous infusion of diazepam: A guide for endoscopy using diazepam

Sugimoto¹,

Furuta²,

Nakamura³

et al. 2008

WJG

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Maintenance time of sedative effects after an intravenous infusion of diazepam: A guide for endoscopy using diazepam

Sugimoto¹,

Furuta²,

Nakamura³

et al. 2008

WJG

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“…Recent investigations by Yasumori et al [17] using various antibodies have co-administration [ 5]. The inhibitory effect of omepra-concluded that diazepam 3-hydroxylation was mainly respect to time and protein concentration was confirmed.…”

Section: Introductionmentioning

confidence: 99%

Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes

Zomorodi

Houston

1996

Brit J Clinical Pharma

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1 The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam ( NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a V max /K m ratio of 0.50-7.26 ml min−1 mg−1 protein. 2 Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K i of 201±89 m was obtained for the 3HDZ pathway (K m /K i ratio of 3.0±0.9). 3 Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar K i s of 121±45 and 188±73 m respectively (K m /K i ratios of 5.2±2.3 and 3.3±1.5 respectively). 4 These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam-omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.Keywords omeprazole diazepam omeprazole sulphone human microsomes in vitro metabolism drug interactions CYP3A CYP2C19

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Principles of Drug Metabolism

Dalvie

Testa

2021

Burger's Medicinal Chemistry and Drug Discovery

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Metabolism is a complex process that involves enzymatic modification of drugs and xenobiotics and is one of the most important determinants of their fate in the body. Although the drug metabolism is considered a process of detoxification, the products of metabolism can play an important role in the pharmacology and toxicology of the parent drug. Studying the metabolism of newly synthesized molecules is a valuable strategy that allows one to identify the underlying problems, such as “soft spots,” or metabolic activation, that affect the systemic exposure of a molecule and safety and efficacy. Early investigative metabolism of new compounds has helped in assessing the bioactivation potential of these candidates and thus, avoid reactive metabolites or put mitigation strategies in place. Metabolism can also lead to pharmacologically active metabolites. These metabolites can have superior pharmacological, pharmacokinetic, and safety profiles compared to their parent drug and can therefore be developed as drugs. This chapter provides an overview of the enzymes involved in the metabolism of xenobiotics and the different metabolic pathways. An attempt has been made to illustrate these principles with pertinent example with a brief review of topics of potential interests to aspiring medicinal chemists namely, the factors that may influence biotransformation or applications to predict the sites of metabolism. While the medicinal chemists are not expected to possess a deep knowledge of the mechanistic aspects, the hope is that the principles outlined in this chapter will assist them in designing a better drug.

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Cytochrome P450 mediated metabolism of diazepam in human and rat: involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner

Cited by 97 publications

References 0 publications

Maintenance time of sedative effects after an intravenous infusion of diazepam: A guide for endoscopy using diazepam

Maintenance time of sedative effects after an intravenous infusion of diazepam: A guide for endoscopy using diazepam

Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes

Principles of Drug Metabolism

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