Pharmacologic and metabolic studies with deuterated zoxazolamine

Tanabe, Masato; Tagg, Josephine; Yasuda, Dennis; LeValley, Susanna E.; Mitoma, Chozo

doi:10.1021/jm00295a008

Cited by 15 publications

(13 citation statements)

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“…Tanabe et al (Masato Tanabe, Tagg, Yasuda, LeValley, & Mitoma, 1970) reported an in vitro KIE of 1.47 for the aryl oxidation of the drug zoxazolamine. However, this result could not be repeated under the same conditions by Tomaszewski et al (Tomaszewski et al, 1975), i.e.…”

Section: Kies For Various P450 Reactionsmentioning

confidence: 99%

Kinetic Deuterium Isotope Effects in Cytochrome P450 Reactions

Guengerich

2017

Methods in Enzymology

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Cytochrome P450 (P450, CYP) research provides many opportunities for the application of kinetic isotope effect (KIE) strategies. P450s collectively catalyze oxidations of more substrates than any other group of enzymes, and C-H bond cleavage is a major feature in a large fraction of these reactions. The presence of a significant primary deuterium KIE is evidence that hydrogen abstraction is at least partially rate-limiting in the reactions, and this appears to be the case in many P450 reactions. The first report of a KIE in (P450-linked) drug metabolism appeared in 1961 (for morphine N-demethylation), and in a number of cases it has been possible to modulate the in vivo metabolism or toxicity of chemicals by deuterium substitution. A number of efforts are in progress to utilize deuterium substitution to alter the metabolism of drugs in an advantageous manner.

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Section: Kies For Various P450 Reactionsmentioning

confidence: 99%

Kinetic Deuterium Isotope Effects in Cytochrome P450 Reactions

Guengerich

2017

Methods in Enzymology

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“…Dideuteriozoxazolamine-4,6-d~ (VI) was synthesized, and the lHMR spectral data were used to establish the exact structure of the compound (182). From i n uiuo studies, it was concluded that there was no isotope effect on the duration of paralysis in rats after drug administration, since the behavior of ordinary and dideuteriozoxazolamine was not significantly different.…”

Section: Miscellaneous Deuterated Compounds Of Biological Importancementioning

confidence: 99%

Studies with Deuterated Drugs

Blake

Crespi

Katz

1975

Journal of Pharmaceutical Sciences

116

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“…The effect was attributed to decreased metabolism of p-tyramine by monoamine oxidases. Several reports that have examined the effect of deuteration on the pharmacokinetic and pharmacodynamic properties of drugs reveal results that include little to no effect (Tanabe et al, 1970;Farmer et al, 1979;Taylor et al, 1983;Burm et al, 1988;Dunsaed et al, 1995); increased systemic exposure, a pharmacodynamic effect, and receptor selectivity (Dyck et al, 1988;Schneider et al, 2006Schneider et al, , 2007; and decreased toxicity (Najjar et al, 1978). However, in these studies the mechanisms underlying the observed effects or lack thereof were not examined.…”

Section: Introductionmentioning

confidence: 99%

Deuterium Isotope Effects on Drug Pharmacokinetics. I. System-Dependent Effects of Specific Deuteration with Aldehyde Oxidase Cleared Drugs

Sharma

Strelevitz²,

Gao³

et al. 2012

Drug Metabolism and Disposition

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ABSTRACT:The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With specifically deuterated model substrates and drugs metabolized by aldehyde oxidase, we demonstrate how knowledge of the enzyme's reaction mechanism, species differences in the role played by other enzymes in a drug's metabolic clearance, and differences in systemic clearance mechanisms are critically important for the pharmacokinetic application of deuterium isotope effects. Ex vivo methods to project the in vivo outcome using deuterated carbazeran and zoniporide with hepatic systems demonstrate the importance of establishing the extent to which other metabolic enzymes contribute to the metabolic clearance mechanism. Differences in pharmacokinetic outcomes in guinea pig and rat, with the same metabolic clearance mechanism, show how species differences in the systemic clearance mechanism can affect the in vivo outcome. Overall, to gain from the application of deuteration as a strategy to alter drug pharmacokinetics, these studies demonstrate the importance of understanding the systemic clearance mechanism and knowing the identity of the metabolic enzymes involved, the extent to which they contribute to metabolic clearance, and the extent to which metabolism contributes to the systemic clearance.

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Pharmacologic and metabolic studies with deuterated zoxazolamine

Cited by 15 publications

References 0 publications

Kinetic Deuterium Isotope Effects in Cytochrome P450 Reactions

Kinetic Deuterium Isotope Effects in Cytochrome P450 Reactions

Studies with Deuterated Drugs

Deuterium Isotope Effects on Drug Pharmacokinetics. I. System-Dependent Effects of Specific Deuteration with Aldehyde Oxidase Cleared Drugs

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