Percutaneous absorption of zinc pyridinethione in monkeys

Gibson, Wade; Calvin, G.

doi:10.1016/s0041-008x(78)80002-7

Cited by 19 publications

(13 citation statements)

References 6 publications

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“…The total percentages of radioactivity absorbed from the 3 test formulations after 72 h fall within the 0.011–4.4% range observed for in vivo animal data for a median deposition of 83 µg/cm 2 ZnPT [5, 8, 9, 12]. On sebum-supplemented skin, the cumulative amount of radioactivity absorbed from the 1% CMC suspension doubled with respect to untreated skin, but still remained within the previously reported range.…”

Section: Discussion/conclusionsupporting

confidence: 82%

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Formulation and Artificial Sebum Effects on the Percutaneous Absorption of Zinc Pyrithione through Excised Human Skin

Rush

Nash

Smith

et al. 2019

Skin Pharmacol Physiol

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Background: Zinc pyrithione (ZnPT) is deposited on the skin as a fine particulate and must reach microorganisms localized in the stratum corneum and hair follicles in molecular form to exert its broad-spectrum antimicrobial/antifungal activity. Dissolution of ZnPT particles followed by molecular speciation results in the organic portion, i.e. pyrithione, being more susceptible to skin penetration than the inorganic component, i.e. zinc, or the chelate itself, i.e. ZnPT. Objectives: To further test the hypothesis that ZnPT skin penetration is rate-limited by dissolution and molecular speciation, the effect of different formulations and artificial sebum on the in vitro percutaneous absorption of radiolabel associated with Zn[¹⁴C]PT was investigated. Method: In vitro penetration of [¹⁴C]PT into and through excised human skin was measured following application of Zn[¹⁴C]PT prepared as suspensions in distinct vehicles including water-based carboxymethylcellulose (CMC), diluted body wash comprised of surfactants, and castor oil, in the presence and absence of artificial sebum. Results: The steady-state flux and cumulative absorption of Zn[¹⁴C]PT increased 4- to 5-fold when deposited from a body wash or castor oil compared to a water-based CMC suspension. Tritiated water flux measured before and after treatment showed that neither the surfactant vehicle nor castor oil significantly altered barrier function versus water alone. An artificial sebum layer on the skin potentiated Zn[¹⁴C]PT and ³H₂O absorption when dosed from both aqueous formulations, but not from castor oil. Conclusion: These data are consistent with the hypothesis that ZnPT percutaneous absorption, as measured by [¹⁴C]PT kinetics, is controlled by particle dissolution and molecular speciation.

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Section: Discussion/conclusionsupporting

confidence: 82%

“…Such outcomes reflect the ability of ZnPT to persist on the surface of the skin, i.e. in the SC and hair follicles [5, 18-20], with only small amounts permeating into the skin and systemic circulation [5, 7-9, 12]. …”

Section: Introductionmentioning

confidence: 99%

Formulation and Artificial Sebum Effects on the Percutaneous Absorption of Zinc Pyrithione through Excised Human Skin

Rush

Nash

Smith

et al. 2019

Skin Pharmacol Physiol

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“…It is important to note that epidermal deposition and retention of ZnPT following topical application has been demonstrated in human skin (Rutherford and Black 1969;Leyden et al 1979). Skin permeation of radiolabeled ZnPT leading to urinary excretion of up to 0.2% of topically applied starting material has been documented in rhesus monkeys (Gibson and Calvin 1978), and ZnPT absorption was increased strongly when the integrity of the stratum corneum was disrupted by abrasion or repeated exposure to concentrated Fig. 6 ZnPT-induced impairment of proliferation, genomic integrity, and ATP homeostasis with upregulated HSP70 expression in human skin melanocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Epidermal deposition and retention of the lipophilic metal chelate ZnPT following topical application has been demonstrated in human skin (Rutherford and Black 1969;Leyden et al 1979), and percutaneous penetration of ZnPT through rat, rabbit, guinea pig, and rhesus monkey skin has been documented earlier (Okamoto et al 1967;Howes and Black 1975;Gibson and Calvin 1978;Guthery et al 2005). Topical safety and toxicity profile of this OTC-drug have been studied to some extent previously, and it has been established that ZnPT does not display a potential for primary irritation or sensitization of human skin (Snyder et al 1965;Brandrup and Menne 1985;Skoulis et al 1993).…”

Section: Introductionmentioning

confidence: 99%

The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells

Lamore

Cabello

Wondrak

2010

Cell Stress and Chaperones

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The differentiated epidermis of human skin serves as an essential barrier against environmental insults from physical, chemical, and biological sources. Zinc pyrithione (ZnPT) is an FDA-approved microbicidal agent used worldwide in clinical antiseptic products, over-thecounter topical antimicrobials, and cosmetic consumer products including antidandruff shampoos. Here we demonstrate for the first time that cultured primary human skin keratinocytes and melanocytes display an exquisite vulnerability to nanomolar concentrations of ZnPT resulting in pronounced induction of heat shock response gene expression and impaired genomic integrity. In keratinocytes treated with nanomolar concentrations of ZnPT, expression array analysis revealed massive upregulation of genes encoding heat shock proteins (HSPA6, HSPA1A, HSPB5, HMOX1, HSPA1L, and DNAJA1) further confirmed by immunodetection. Moreover, ZnPT treatment induced rapid depletion of cellular ATP levels and formation of poly (ADP-ribose) polymers. Consistent with an involvement of poly(ADP-ribose) polymerase (PARP) in ZnPT-induced energy crisis, ATP depletion could be antagonized by pharmacological inhibition of PARP. This result was independently confirmed using PARP-1 knockout mouse embryonic fibroblasts that were resistant to ATP depletion and cytotoxicity resulting from ZnPT exposure. In keratinocytes and melanocytes, single-cell gel electrophoresis and flow cytometric detection of γ-H2A.X revealed rapid induction of DNA damage in response to ZnPT detectable before general loss of cell viability occurred through caspase-independent pathways. Combined with earlier experimental evidence that documents penetration of ZnPT through mammalian skin, our findings raise the possibility that this topical antimicrobial may target and compromise keratinocytes and melanocytes in intact human skin.

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“…Following topical application in human skin, epidermal deposition and retention of the lipophilic metal chelate ZnPT has been demonstrated (Rutherford and Black 1969; Leyden et al 1979). Moreover, percutaneous penetration of ZnPT has been observed in relevant animal models of human skin (Okamoto et al 1967; Howes and Black 1975; Gibson and Calvin 1978; Guthery et al 2005). …”

Section: Introductionmentioning

confidence: 99%

Zinc pyrithione impairs zinc homeostasis and upregulates stress response gene expression in reconstructed human epidermis

Lamore

Wondrak

2011

Biometals

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Zinc ion homeostasis plays an important role in human cutaneous biology where it is involved in epidermal differentiation and barrier function, inflammatory and antimicrobial regulation, and wound healing. Zinc-based compounds designed for topical delivery therefore represent an important class of cutaneous therapeutics. Zinc pyrithione (ZnPT) is an FDA-approved microbicidal agent used worldwide in over-the-counter topical antimicrobials, and has also been examined as an investigational therapeutic targeting psoriasis and UVB-induced epidermal hyperplasia. Recently, we have demonstrated that cultured primary human skin keratinocytes display an exquisite sensitivity to nanomolar ZnPT concentrations causing induction of heat shock response gene expression and poly(ADP-ribose) polymerase (PARP)-dependent cell death (Cell Stress Chaperones 15:309–322, 2010). Here we demonstrate that ZnPT causes rapid accumulation of intracellular zinc in primary keratinocytes as observed by quantitative fluorescence microscopy and inductively coupled plasma mass spectrometry (ICP-MS), and that PARP activation, energy crisis, and genomic impairment are all antagonized by zinc chelation. In epidermal reconstructs (EpiDerm™) exposed to topical ZnPT (0.1–2% in Vanicream™), ICP-MS demonstrated rapid zinc accumulation, and expression array analysis demonstrated upregulation of stress response genes encoding metallothionein-2A (MT2A), heat shock proteins (HSPA6, HSPA1A, HSPB5, HSPA1L, DNAJA1, HSPH1, HSPD1, HSPE1), antioxidants (SOD2, GSTM3, HMOX1), and the cell cycle inhibitor p21 (CDKN1A). IHC analysis of ZnPT-treated EpiDerm™ confirmed upregulation of Hsp70 and TUNEL-positivity. Taken together our data demonstrate that ZnPT impairs zinc ion homeostasis and upregulates stress response gene expression in primary keratinocytes and reconstructed human epidermis, activities that may underlie therapeutic and toxicological effects of this topical drug.

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Percutaneous absorption of zinc pyridinethione in monkeys

Cited by 19 publications

References 6 publications

Formulation and Artificial Sebum Effects on the Percutaneous Absorption of Zinc Pyrithione through Excised Human Skin

Formulation and Artificial Sebum Effects on the Percutaneous Absorption of Zinc Pyrithione through Excised Human Skin

The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells

Zinc pyrithione impairs zinc homeostasis and upregulates stress response gene expression in reconstructed human epidermis

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