Coding and non-coding polymorphisms in alcohol dehydrogenase alters protein expression and alcohol-associated erythema.

Ethanol (EtOH), isopropyl alcohol (IPA), and propylene glycol (PG) increase topical drug delivery, but are sometimes associated with erythema. A potential genetic basis for alcohol-associated erythema was investigated as the function of polymorphisms in coding and non-coding regions of class IB alcohol dehydrogenase (ADHIB) and evaluated for altered gene expression in vitro and metabolic activity in vivo via altered skin blood flow (Doppler velocimeter) and erythema (reflectance colorimeter a*) following topical challenge to 5 M EtOH, IPA, PG, and butanol (ButOH). Promoter polymorphisms G-887A and C-739T and exon G143A form eight ADHIB haplotypes with different frequencies in Caucasians vs Asians and exhibit variable gene expression and metabolic activity. Polymorphisms C-739T and G-887A independently alter gene expression, which is further increased by IPA and PG, but not EtOH or ButOH. EtOH and ButOH increase erythema as a function of skin blood flow. IPA increases skin blood flow without erythema and PG increased erythema with decreased skin blood flow, all as a function of ADHIB haplotype. PG-induced erythema was uniquely associated with tumor necrosis factor-alpha expression. Thus, erythema following alcohol exposure is alcohol type specific, has a pharmacogenetic basis related to ADHIB haplotype and can be functionally evaluated via Doppler velocimetry and reflectance colorimetry in vivo.

Disposition and pharmacokinetics of a lubricant contaminant, 2,6-di-tert-butyl 4-nitrophenol, in grafted human skin.

Disposition and uptake/elimination profiles of topical 2,6-di-t-butyl, 4-nitrophenol (DBNP), the nitrated metabolite of an antioxidant additive of lubricant and hydraulic fluids was quantified in human skin grafted on athymic mice after a single topical 75 microg dose in corn oil. DBNP was quantified throughout the stratum corneum (SC), epidermis (E) and dermis (D) in punch biopsies collected from treated skin 0.5, 1, 2, 4, 8 and 24 h after application. SC samples were harvested from the treated skin with 20 adhesive discs. E and D were generated from the biopsy using a manual sectioning method. Detectable DBNP concentrations were measured in all skin compartments at all time points investigated. The Cmax of DBNP in SC was 1663 +/- 602 microg cm(-3), and approximately 30 and approximately 300 fold greater than the Cmax for E and D, respectively. Tmax occurred at 1.0, 0.5 and 1.0 in the SC, E and D, respectively. Over a 24 h interval (AUC0-24 h) there was 52 and 520 fold more DBNP in the SC than E and D, respectively. The elimination half-life of DBNP was 11 h from the SC and 9 h from both E and D. Thus, DBNP was quickly absorbed into the outermost layer of skin and established a steep concentration profile through human skin. The data are consistent with the vast majority of DBNP remaining on the surface (77%) or within human skin (15%) in vivo with only 0.2% of the DBNP dose quantified in the systemic blood circulation.

Assessment of dermatopharmacokinetic approach in the bioequivalence determination of topical tretinoin gel products.

BACKGROUND: A new dermatopharmacokinetic (DPK) approach has been proposed for bioequivalence determination of topical drug products by comparing the drug content kinetics in stratum corneum. OBJECTIVE: We sought to establish any correlation between clinical safety/efficacy and DPK approach in bioequivalence determination of tretinoin gel 0.025%. METHODS: Tretinoin and isotretinoin were quantified in human volar forearm stratum corneum as a function of time with 3 tretinoin gel 0.025% products in 49 patients. Stratum corneum layers were harvested using multiple adhesive disks, which were subsequently extracted and quantified for both isomers by high-performance liquid chromatography. RESULTS: Products with similar composition and therapeutic equivalence were found bioequivalent, and products with different composition and clinical profiles were found bioinequivalent by DPK methodology. CONCLUSIONS: There is a direct correlation between DPK parameters in healthy patients and clinical safety/efficacy of tretinoin gel products in patients with acne. Data support the use of DPK parameters and methodology in the bioequivalence assessment of topical tretinoin gel products.