Zinc pyridinethione: Urinary metabolites of zinc pyridinethione in rabbits, rats, monkeys, and dogs after oral dosing

Jeffcoat, A; Gibson, Wade; Rodríguez, Pedro; Turan, T. S.; Hughes, Philip F.; Twine, Margaret

doi:10.1016/0041-008x(80)90139-8

Cited by 19 publications

(8 citation statements)

References 16 publications

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“…We are aware of only a handful of reports of S-linked glucuronides in the literature: Lindsay et al (1977), Jeffcoat et al (1980), Bieder et al (1983), Nakaoka et al (1989), Peffer et al (1991), Bakke et al (1992), Smith et al (1992), and Fukuoka et al (1995). Of these reports, only the groups of Jeffcoat, Nakaoka, and Smith have described NMR data in support of their findings, although none give complete proton and carbon information.…”

Section: Fig 2 Partial Hmbc Spectrum and Structure Of Ar-c133611xx mentioning

confidence: 99%

“…The chemical shifts of the anomeric proton and carbon are usually the key to determining the site of attachment of a glucuronide moiety. Comparison of the carbon chemical shifts of C1Ј of AR-C133611XX glucuronide with the few published examples shows good agreement [AR-C133611XX glucuronide, 87.7 ppm; 2-pyridinethiol-S-glucuronide, 84.1 ppm; N-oxide of this, 82.6 ppm (Jeffcoat et al, 1980); S-glucuronide metabolite of malotilate, 87 ppm (Nakaoka et al, 1989)]. The proton chemical shift of the anomeric proton is significantly more shielded than in those S-glucuronides previously reported [AR-C133611XX glucuronide, 4.90 ppm; S-glucuronide metabolite of malotilate, 5.96 ppm (Nakaoka et al, 1989); S-glucuronide of 4-nitrothiophenol, 5.62 ppm (Smith et al, 1992)].…”

Section: Fig 2 Partial Hmbc Spectrum and Structure Of Ar-c133611xx mentioning

confidence: 99%

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NMR IDENTIFICATION OF AN S-LINKED GLUCURONIDE OF A TRIAZOLE THIONE FORMED IN VITRO

Martin

Lewis²,

Bonnert³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The metabolism of 3-{[3-(2-Chlorophenyl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-1-yl]methyl}benzonitrile (AR-C133611XX) was studied in isolated dog hepatocytes. The major metabolite of AR-C133611XX was characterized by high performance liquid chromatography-mass spectrometry and NMR and found to be the product of direct glucuronidation. Evidence from 1 H and 13 C-NMR chemical shifts and a long-range proton carbon correlation experiment was used to deduce that glucuronidation had taken place on the sulfur atom. Full NMR data on this unusual metabolite is presented. Substitution or replacement of the sulfur atom resulted in a significant decrease in the observed rate of glucuronidation.

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Section: Fig 2 Partial Hmbc Spectrum and Structure Of Ar-c133611xx mentioning

confidence: 99%

Section: Fig 2 Partial Hmbc Spectrum and Structure Of Ar-c133611xx mentioning

confidence: 99%

NMR IDENTIFICATION OF AN S-LINKED GLUCURONIDE OF A TRIAZOLE THIONE FORMED IN VITRO

Martin

Lewis²,

Bonnert³

et al. 2003

Drug Metab Dispos

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“…We investigated the effect of EDTA on ZnPT absorption in shampoo formulations. PT and MSP, among ZnPT metabolites (19,20), are used as indicators of systemic ZnPT exposure. In this study, a direct LC-MS/MS method was developed for quantitative determination of ZnPT, PT, and MSP concentrations in rat plasma and urine.…”

Section: Discussionmentioning

confidence: 99%

Effect of Combined Exposure to EDTA and Zinc Pyrithione on Pyrithione Absorption in Rats

Jung

Lee

et al. 2019

ToxicolRes

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Zinc pyrithione (ZnPT) is a coordination complex of zinc and has been used widely as an anti-dandruff agent in shampoos. Many shampoos contain both ZnPT and EDTA, a chelating agent speculated to increase ZnPT absorption, thereby raising concerns about neurotoxicity. Here, we investigated the effect of EDTA on ZnPT absorption by direct comparison of ZnPT and pyrithione (PT) concentrations in shampoo formulations, and by pharmacokinetic analysis of ZnPT, PT, and 2-methanesulfonylpyridine (MSP), the main ZnPT metabolite, in rat plasma or urine following exposure to shampoo containing ZnPT alone or a combination of ZnPT and EDTA. Approximately 17.3% of ZnPT was converted to PT by the addition of EDTA in the shampoo formulation. Plasma ZnPT and PT concentrations were not measured up to 24 hr after treatment with shampoo containing 1% ZnPT or 1% ZnPT + 2% EDTA in all rats. However, PT amount in 24-hr urine sample, MSP concentration in plasma, and MSP amount in 24-hr urine sample were approximately 4-, 2.6-, and 2.7-fold higher, respectively, in the 1% ZnPT + 2% EDTA shampoo group than in the 1% ZnPT shampoo group. As confirmed by the formulation analysis and in vivo pharmacokinetic analysis, the exposure of ZnPT could be increased by the absorption of PT due to partial dissociation of ZnPT into PT.

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“…The synthetic glucuronide 3 that was determined to be S-glucuronide was found to have retention times identical to that of metabolite M1 under all 10 HPLC conditions. Literature reports of glucuronide conjugation through an S-linkage are rare (Jeffcoat et al, 1980;Nakaoka et al, 1989;Smith et al, 1992;Ethell et al, 2003;Martin et al, 2003), with little data available on their structural characterization or the UDP-glucuronosyltransferases (UGTs) catalyzing their formation. N-and O-glucuronides are more commonly observed (Green and Tephly, 1998;Hawes, 1998;Kuehl and Murphy, 2003;Tricker, 2003).…”

Section: Resultsmentioning

confidence: 99%

NMR CHARACTERIZATION OF AN S-LINKED GLUCURONIDE METABOLITE OF THE POTENT, NOVEL, NONSTEROIDAL PROGESTERONE AGONIST TANAPROGET

Keating

McConnell²,

Zhang³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Tanaproget is a first-in-class nonsteroidal progesterone receptor agonist that is being investigated for use in contraception. A major in vitro and in vivo metabolite of tanaproget formed in humans was initially characterized as a glucuronide of tanaproget. However, whether the glucuronide was linked to the nitrogen or sulfur of the benzoxazine-2-thione group in tanaproget could not be determined by liquid chromatography/mass spectrometry (LC/MS) and LC-tandem mass spectrometry analysis. To obtain additional structural details for this metabolite, additional quantities were generated from rat liver microsomal incubations and purified by high-performance liquid chromatography (HPLC) for NMR analysis. The NMR data for the metabolite confirmed that the glucuronide was covalently bound to either the sulfur or the nitrogen of the benzoxazine-2-thione moiety. The lack of key through-bond (scalar) and through-space (dipolar) one-dimensional (1D) and twodimensional (2D) NMR couplings and correlations in the metabolite spectra (due primarily to low sample concentration) precluded an unambiguous structure elucidation. Subsequent synthesis of the S-and N-glucuronides of tanaproget from tanaproget facilitated the unambiguous regio-and stereochemical assignment of the metabolite by comparison of 1D NMR chemical shifts and scalar coupling constants, 2D NMR correlations, and HPLC and LC/MS characteristics between the synthetic compounds and the metabolite. From extensive comparison of the spectral and chromatographic data of the microsomally derived metabolite and the synthetic compounds, the metabolite has been determined to be the S-(␤)-D-glucuronide of tanaproget.Tanaproget is a potent, first-in-class nonsteroidal progesterone receptor agonist being investigated at Wyeth for use in contraception (Fensome et al., 2005;Zhang et al., 2005). Earlier studies indicated that a major conjugated metabolite (Ͼ10%), referred to here as M1, was formed in rat and human liver microsomal incubations, and initially characterized by LC/MS as a glucuronide of tanaproget. The glucuronic acid group was proposed to be either on the nitrogen or the sulfur of the benzoxazine-2-thione moiety of tanaproget (1, Scheme 1). Oxidative metabolism represented a minor metabolic pathway of 1 in both in vitro and in vivo studies.Analysis of the initial NMR data of M1 from rat liver microsomes confirmed that the glucuronide was covalently bound to either the Sor the N-form of the benzoxazine-2-thione moiety. However, due to an insufficient amount (approximately a few micrograms) of the sample in solution, we could not record complete scalar and dipolar 1D and 2D NMR couplings and correlations for an unambiguous structure elucidation. The NMR analysis was especially challenging because of the lack of protons in the benzoxazine-2-thione moiety, particularly in the scenario of an S-glucuronide conjugate of tanaproget, since most heteronuclear correlations between the sugar and the parent molecule would be too long range to be observed.Because of the ch...

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Zinc pyridinethione: Urinary metabolites of zinc pyridinethione in rabbits, rats, monkeys, and dogs after oral dosing

Cited by 19 publications

References 16 publications

NMR IDENTIFICATION OF AN S-LINKED GLUCURONIDE OF A TRIAZOLE THIONE FORMED IN VITRO

NMR IDENTIFICATION OF AN S-LINKED GLUCURONIDE OF A TRIAZOLE THIONE FORMED IN VITRO

Effect of Combined Exposure to EDTA and Zinc Pyrithione on Pyrithione Absorption in Rats

NMR CHARACTERIZATION OF AN S-LINKED GLUCURONIDE METABOLITE OF THE POTENT, NOVEL, NONSTEROIDAL PROGESTERONE AGONIST TANAPROGET

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