title: Ga(III) complexes--the effect of metal coordination on potential systemic absorption after topical exposure.
abstract: The handling of elemental gallium is not thought to be harmful, but this assumption does not consider metal coordination which readily occurs in physiological fluids. The aim of this work was to determine Ga(III) coordination behaviour in simple solutions and assess the effects of complex formation upon skin permeation in vitro. Ga(III) coordination was modelled using metal-ligand stability constants in silico and the permeation of the metal through human and porcine skin determined using four test conditions. Ga(III) was presented to the skin as: (1) Ga³+ ions; (2) a -ve citrate complex (Ga(neg)); (3) a mixture of +ve and -ve complexes (Ga(mix)) and (4) a mixture of +ve hydroxide complexes (Ga(pos)). The permeability coefficient (Kp) of Ga(III) through human skin increased by almost 2 orders of magnitude when applied as free Ga³+ ions or a Ga(neg) complex (the two most water soluble complexes), compared to Ga(mix) or Ga(pos). This trend was not well modelled by porcine skin which proved to be less of a barrier to Ga(III) permeation compared to human skin (Kp=2 x 10⁻³ ± 2 x 10⁻⁴ cm h⁻¹). Given the significant transdermal bioavailablity of Ga(III) demonstrated by this study, it would appear prudent to re-evaluate the dermal toxicity of this metal.
authors.affiliation: Pharmaceutical Science Research Division, King's College London, 150A Stamford Street, Waterloo, London SE19NN, UK.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Staff
authors.forename: Marc B
authors.initials: MB
authors.lastname: Brown
authors.forename: Robert P
authors.initials: RP
authors.lastname: Chilcott
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Jones
authors.forename: Xiao L
authors.initials: XL
authors.lastname: Kong
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D056831:Coordination Complexes / Q000737:chemistry* / Q000493:pharmacokinetics*; D005260:Female; D005708:Gallium / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D010539:Permeability / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology; D013552:Swine
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005708:Gallium; C027235:gallium nitrate