Biotransformation of Drugs in Human Skin

Svensson, Craig K.

doi:10.1124/dmd.108.024794

Cited by 86 publications

(61 citation statements)

References 31 publications

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“…Skin being the largest organ in the body has two major functions linked to the clearance of xenobiotics. They involve the xenobiotic-metabolizing enzymes 80 and the sweat glands. 81 Most importantly, some toxic compounds (for example, nicotinamide 60 ) cannot be effectively excreted through urine in its natural form, but can be eliminated through sweat.…”

Section: Proposed Mechanism For the Effects Of Methyl Consumersmentioning

confidence: 99%

Dietary methyl-consuming compounds and metabolic syndrome

Zhou

et al. 2011

Hypertens Res

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The metabolic syndrome, a major risk factor for type 2 diabetes and cardiovascular disease, is a cluster of metabolic abnormalities including obesity, insulin resistance, hypertension and dyslipidemia. Although systemic oxidative stress and aberrant methylation status are known to have important roles in the development of metabolic syndrome, how they occur remains unclear. The metabolism of methyl-consuming compounds generates reactive oxygen species and consumes labile methyl groups; therefore, a chronic increase in the levels of methyl-consuming compounds in the body can induce not only oxidative stress and subsequent tissue injury, but also methyl-group pool depletion and subsequent aberrant methylation status. In the past few decades, the intake amount of methyl-consuming compounds has substantially increased primarily due to pollution, food additives, niacin fortification and high meat consumption. Thus, increased methyl consumers might have a causal role in the development and prevalence of metabolic syndrome and its related diseases. Moreover, factors that decrease the elimination/ metabolism of methyl-consuming compounds and other xenobiotics (for example, sweat gland inactivity and decreased liver function) or increase the generation of endogenous methyl-consuming compounds (for example, mental stress-induced increase in catecholamine release) may accelerate the progression of metabolic syndrome. Based on current nutrition knowledge and the available evidence from epidemiological, ecological, clinical and laboratory studies on metabolic syndrome and its related diseases, this review outlines the relationship between methyl supply-consumption imbalance and metabolic syndrome, and proposes a novel mechanism for the pathogenesis and prevalence of metabolic syndrome and its related diseases.

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Section: Proposed Mechanism For the Effects Of Methyl Consumersmentioning

confidence: 99%

Dietary methyl-consuming compounds and metabolic syndrome

Zhou

et al. 2011

Hypertens Res

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“…Prior reviews had attributed this toxicity to the biotransformation of the drugs in human skin and their active metabolites [7,8]. Recent investigations have documented the presence of cytochrome P450 (CYP) enzymes in the skin [9].…”

Section: Introductionmentioning

confidence: 99%

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Burkhart

Abernethy

Jackson³

2015

J. Med. Toxicol.

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Drug features that are associated with StevensJohnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with druginduced adverse events. The information gained may contribute to systems biology disease models.

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“…This skin metabolism may have an effect on the percutaneous penetration and delivered dose of xenobiotics administered by the transdermal route [10,11]. Skin absorption/permeation characteristics can be studied by using a reconstructed human epidermis (RHE), which is a normal (nontransformed), human cell-derived, metabolically active, 3-dimensional organotypic in vitro skin model.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Metabolism of Donepezil in Rat, Mini-Pig and Human, Following Oral and Transdermal Administration, and in an In Vitro Model of Human Epidermis

Davis¹,

Murgasova²

2012

J Drug Metab Toxicol

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Donepezil hydrochloride is a centrally acting, reversible acetyl cholinesterase inhibitor approved for Alzheimer's disease therapy. Donepezil is marketed as an oral tablet but a transdermal patch may have advantages as an alternate therapy. To determine whether the transdermal route alters known donepezil metabolism, this study compared plasma metabolites of donepezil hydrochloride with two routes of drug delivery, transdermal and oral, in three species; rat, mini-pig and human. The utility of a reconstituted human epidermis (RHE) in vitro model for transdermal drug biotransformation was also evaluated. In addition to donepezil, structures from three metabolic pathways were detectable in each matrix: 1) O demethylation (M1/M2; 2) N-dealkylation (M4); 3) N-oxidation (M6) utilizing LC/quadrupole-Ion trap MS/MS. In rats and humans, including RHE, the mean concentration levels of the donepezil and metabolites for both routes were found in the following order: donepezil>M4>M6>isomeric M1/M2 whilst in the pig, the order was the following: donepezil>M6>isomeric M1/M2>M4. Overall, there were no substantial differences in the plasma profiles between the rat and human. Donepezil metabolites were detectable in mini-pigs after both oral and transdermal administration, however, the concentrations varied from both rat and human. RHE showed quantitative and qualitative similarities between the metabolites produced in vitro with those found in human plasma after transdermal application. Thus, the data from the present study demonstrate that similar metabolites are found between the three species with rat most closely resembling humans and that the RHE model is a potentially valuable model to predict dermal metabolism.

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Biotransformation of Drugs in Human Skin

Cited by 86 publications

References 31 publications

Dietary methyl-consuming compounds and metabolic syndrome

Dietary methyl-consuming compounds and metabolic syndrome

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Comparison of Metabolism of Donepezil in Rat, Mini-Pig and Human, Following Oral and Transdermal Administration, and in an In Vitro Model of Human Epidermis

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