Metabolic disposition of pyrithiones

doi:10.1016/S0272-0590(83)80137-7

Fundamental and Applied Toxicology

Volume 3, Issue 4, July–August 1983, Pages 256-263

Fundamental and Appl...

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Abstract

The urinary pattern of pyrithione metabolites in urine of the rat, rabbit and rhesus monkey was similar to that of the swine after iv, administration of sodium pyrithione (Sodium Omadine®) and the magnesium sulfate adduct of 2,2′-dithio-bis(pyridine-1-oxide), (Omadine® MDS). The major metabolite accounting for 80% or more of the metabolites in urine was the S-glucuronide of 2-mercaptopyridine-N-oxide. After Omadine® MDS administration, three transient metabolites and one persistent metabolite were observed in the plasma. The transient metabolites were tentatively identified as 2-methylthiopyridine-N-oxide, 2-methylsulfinylpyridine and 2-methylsulfinylpyridine-N-oxide. 2-Methylsulfonylpyridine was the only metabolite observed in the plasma 16 hr after Omadine® administration. This metabolite could be detected 14 days after rats were treated repeatedly with a shampoo formulation containing Omadine MDS.

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UHPLC-MS/HRMS method for the quantitation of pyrithione metabolites in human urine
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Other minor metabolites reported have included 2-pyridinesulfonic acid-1-oxide [11], 2,2′-pyridinedisulfide [11] and 2-pyridinethiol-l-oxide-S-glucoside [12]. These urinary metabolites have never been studied in humans following application of pyrithione salts or pyrithione containing products but have been examined in animal species using liquid chromatography isolation followed by radiochemical, mass spectrometry, and nuclear magnetic resonance spectroscopy for identification [8–11]. To better establish the primary detoxification pathway of pyrithione between animals and humans, a selective quantitative method was developed to determine if PTG and ThPG were found in urine of humans following topical application of a ZnPT containing shampoo product.
Pyrithione glucuronide (PTG) and 2-thiopyridine glucuronide (ThPG) have been reported to be the major urinary metabolites in multiple animal species following administration of zinc pyrithione (ZnPT). However, the formation of these metabolites has never been confirmed in humans. A simple and rugged ultra-high-performance liquid chromatography high resolution mass spectrometry (UHPLC-MS/HRMS) method was developed and validated for the quantification of PTG and ThPG to investigate human metabolism of pyrithione following topical application of ZnPT as a shampoo. A UHPLC-MS/HRMS method was required due to the matrix interferences that were observed with the typical industry standard HPLC/tandem mass spectrometry (LC-MS/MS) methodology based on nominal mass triple quadrupole (QQQ) platform approach. Using UPLC-MS/HRMS, both PTG and ThPG were identified in human urine following topical application of ZnPT. The presence of these human urinary metabolites of pyrithione are consistent with findings from earlier studies in multiple animal species and suggest the metabolism of pyrithione is similar amongst those mammalian species studied.
Incorporating new approach methodologies in toxicity testing and exposure assessment for tiered risk assessment using the RISK21 approach: Case studies on food contact chemicals
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What happens in the skin? Integrating skin permeation kinetics into studies of developmental and reproductive toxicity following topical exposure
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Diethylene glycol monoethyl ether was used to dissolve CAP in Chanda et al’s study because this is the solvent contained in the NGX-400 capsaicin patch designed for human use [246,301], but capsaicin is also used as a fungicide and insecticide [302]. Omadine MDS was dissolved in shampoo blank because it is an antimicrobial and preservative used in shampoos and cosmetic products [303]. The use of olive oil as a vehicle for 4-MBC [278] mimics the lipophilic nature of sunscreen components.
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Pyrithione and 8-hydroxyquinolines transport lead across erythrocyte membranes
2009, Translational Research
Citation Excerpt :
As shown in Fig 6, a single centrifugation resulted in virtually complete recovery of added sodium pyrithione in the plasma. Animal studies have shown that sodium pyrithione metabolites are rapidly excreted in the urine after intravenous injection,22 which is consistent with portioning of this compound into the extracellular space. It has long been known that virtually all lead in whole blood is found in erythrocytes23,24 and enters via the anion exchanger.25
Acute and chronic lead poisoning remains a significant health problem. Although chelating agents can bind to plasma lead, they cannot cross cell membranes where the total body lead burden resides, and are thus inefficient at reducing the total body lead burden. Recently, calcium and sodium ionophores have been shown to transport lead across cell membranes providing a novel method for reducing total body lead stores. We recently found that clioquinol, an 8-hydroxyquinoline derivative, can act as a zinc ionophore. We postulated that zinc ionophores might also be able to transport lead across biological membranes. To study this, we loaded lead in vitro into human erythrocytes and then studied the ability of zinc ionophores to transport lead into the extracellular space, where it was trapped with a lead chelator. Using inductively coupled plasma mass spectrometry (ICP-MS), we found that several 8-hydroxyquinoline derivatives, as well as the zinc and sodium salts of pyrithione (N-hydroxypyridine-2-thione), reduced erythrocyte lead content. The water-soluble compound, sodium pyrithione, was able to reduce lead in citrated whole blood, without partitioning into the erythrocytes. These results indicate that two classes of zinc ionophores can transport lead across a biological membrane, and they confirm that these ionophores are not cation-specific. Lead ionophores may prove useful in mobilizing lead into the extracellular space, thereby improving the efficacy of chelation therapy, in vivo or ex vivo.
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Pyrithione biocides are currently viewed as a major prospect for the replacement of tributyltin antifoulants in ship paints. The chromatographic behavior of 1-hydroxy-2-pyridinethione (pyrithione, PT), bis(2-pyridinyl)disulfide 1,1′-dioxide (PT₂), and the metal complexes zinc [Zn(PT)₂], iron [Fe(PT)₃] and copper [Cu(PT)₂] pyrithione, were investigated by means of UV–vis spectroscopy, ESI-MSⁿ, HPLC-DAD and HPLC-ESI-MSⁿD. This revealed transformations of the analytes, which affect the development of adequate methods for species or environmental analysis of pyrithiones. PT transforms into copper- or iron- containing complexes and/or the oxidation product PT₂, depending on the type of the stationary phase used in chromatographic analysis. Speciation complicates direct chromatography of [Zn(PT)₂] and [Fe(PT)₃].
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^*: A preliminary communication was presented at the 21st Society of Toxicology Meeting, Boston, MA, February 22, 1982.

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Metabolic disposition of pyrithiones*

Abstract

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.