Isotopic Effect Study of Propofol Deuteration on the Metabolism, Activity, and Toxicity of the Anesthetic

Helfenbein, Julie; Lartigue, Claire; Noirault, E. Miot; Azim, El Mostapha; Legailliard, J; Galmier, Marie-Josèphe; Madelmont, J. C.

doi:10.1021/jm020864q

Cited by 54 publications

(31 citation statements)

References 21 publications

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“…For instance, two isopropyl groups in 2,6-diisopropylphenol (propofol, is a short-acting, intravenously administered hypnotic agent) [58] are equivalent in chemical shifts [59] because of the low rotational barrier. Therefore, it seems that the appearance of approximately two doublets in 1 H NMR spectrum of 1c (before adding D 2 O) either attributed to the hindrance effect between two isopropyls and tetrazole groups upon phenyl ring and restricted rotation around ether linkage bonds in 1c or presumably to the equilibrium mixture of 1H-and 2H-tautomers that slightly have enough life time in NMR time scale.…”

Section: Resultsmentioning

confidence: 99%

Isotopic effect on tautomeric behavior of 5‐(2,6‐disubstituted‐aryloxy)‐tetrazoles

Pesyan

2011

Magnetic Reson in Chemistry

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Isotopic effect on tautomeric behaviors of the synthesized 5-phenoxy- (1a), 5-(2,6-dimethylphenoxy)-(1b), 5-(2,6-diisopropylphenoxy)-(1c), 5-(2,6-dimethoxyphenoxy)-(1d) and 5-(4-methylphenoxy)-tetrazole (1e) were investigated in DMSO-d6 by adding one drop of D2O. Among 1a-e, 1a, 1d and 1e show small rotational barrier around C5-O1 and O1-C6 while in 1b and 1c there are distinguishable rotational barrier about that bonds. The (1)H NMR spectra of 1b and 1c show slightly different chemical shifts for two methyl and isopropyl groups on those phenyl ring, respectively, while the chemical shifts difference (Δδ) between two methyl and two isopropyl groups were enhanced by adding D2O. The (13)C NMR spectra of 1b show two overlapped singlets for methyl groups after adding D2O. Representatively, the calculations of compound 1c were performed with GAUSSIAN-03 and the rotational barrier about C5-O1 and between isopropyl group and phenyl ring in 1c was calculated with B3LYP/6-31G(d) basis set.

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Section: Resultsmentioning

confidence: 99%

Isotopic effect on tautomeric behavior of 5‐(2,6‐disubstituted‐aryloxy)‐tetrazoles

Pesyan

2011

Magnetic Reson in Chemistry

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“…This can often increase drug exposure and reduce drug toxicity . However, deuterium replacement strategy may be confounded by metabolic switching and other metabolic pathways in vivo, for example, deuterated Propofol and Imatinib …”

Section: Introductionmentioning

confidence: 99%

Effect of N‐methyl deuteration on pharmacokinetics and pharmacodynamics of enzalutamide

Pang

Peng

Chen

2017

Labelled Comp Radiopharmac

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Enzalutamide, a second-generation antiandrogen, has been developed for the treatment of castration-resistance prostate cancer. We synthesized the deuterated analogues 6 and found that it showed higher drug exposure and thus stronger antitumor potency in preclinical settings. Compound 6 is being developed clinically for the potential to be differentiated from enzalutamide through reduced dosages and a higher safety margin.

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“…Many factors may confound this approach, including the contribution to in vivo metabolism by enzymes which do not rely on C-H bond breakage. No isotope effect was observed after administration of deuterated propofol to mice (Helfenbein et al, 2002); this may be attributed to the fact that glucuronidation accounts for a significant proportion of propofol metabolism (Simons et al, 1988). Contribution to in vivo clearance by nonmetabolic elimination mechanisms (urinary and/or biliary excretion of unchanged drug) may also attenuate in vivo deuterium isotope effects; biliary excretion of zoniporide (;40% of dose) is likely to contribute to the lack of isotope effects observed for this compound in rats (Sharma et al, 2012).…”

Section: Discussionmentioning

confidence: 93%

Application of a Deuterium Replacement Strategy to Modulate the Pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole, a Novel CRF1 Antagonist

Stringer

Williams

Picard

et al. 2014

Drug Metabolism and Disposition

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Deuterium isotope effects were evaluated as a strategy to optimize the pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo [5,1-b]oxazole (NVS-CRF38), a novel corticotropin-releasing factor receptor 1 (CRF 1 ) antagonist. In an attempt to suppress O-demethylation of NVS-CRF38 without losing activity against the CRF 1 receptor, the protons at the site of metabolism were replaced with deuterium. For in vitro and in vivo studies, intrinsic primary isotope effects (K H /K D ) were determined by the ratio of intrinsic clearance (CL int ) obtained for NVS-CRF38 and deuterated NVS-CRF38. In vitro kinetic isotope effects (K H /K D ) were more pronounced when CL int values were calculated based on the rate of formation of the O-desmethyl metabolite (K H /K D ∼7) compared with the substrate depletion method (K H /K D ∼2). In vivo isotope effects were measured in rats after intravenous (1 mg/kg) and oral (10 mg/kg) administration. For both administration routes, isotope effects calculated from in vivo CL int corresponding to all biotransformation pathways were lower (K H /K D ∼2) compared with CL int values calculated from the O-demethylation reaction alone (K H /K D ∼7). Comparative metabolite identification studies were undertaken using rat and human microsomes to explore the potential for metabolic switching. As expected, a marked reduction of the O-demethylated metabolite was observed for NVS-CRF38; however, levels of NVS-CRF38's other metabolites increased, compensating to some extent for the isotope effect.

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Isotopic Effect Study of Propofol Deuteration on the Metabolism, Activity, and Toxicity of the Anesthetic

Cited by 54 publications

References 21 publications

Isotopic effect on tautomeric behavior of 5‐(2,6‐disubstituted‐aryloxy)‐tetrazoles

Isotopic effect on tautomeric behavior of 5‐(2,6‐disubstituted‐aryloxy)‐tetrazoles

Effect of N‐methyl deuteration on pharmacokinetics and pharmacodynamics of enzalutamide

Application of a Deuterium Replacement Strategy to Modulate the Pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole, a Novel CRF1 Antagonist

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