A quantitative assessment of protoporphyrin IX metabolism and phototoxicity in human skin following dose-controlled delivery of the prodrugs 5-aminolaevulinic acid and 5-aminolaevulinic acid-n-pentylester

Background Topical 5-aminolaevulinic acid (ALA) is widely used in photodyna mic therapy (PDT) to generate protoporphyrin IX (PpIX) in the skin. However , other prodrugs may be more effective. Objectives The pharmacokinetics of ALA- and ALA-n-pentylester-induced PpIX, together with the phototoxicity after PDT, were compared in human skin in vivo, using iontophoresis as a quantitative drug delivery system. Methods A series of six increasing doses of equimolar prodrug solutions was iontophoresed into normal skin of the upper inner arms of 20 healthy subje cts. The kinetics of PpIX metabolism in skin (n = 4) and the response to li ght exposure, performed at 4.5 h (n = 6) and 6 h (n = 10) after application , were assessed by skin surface PpIX fluorescence and postirradiation eryth ema. Results ALA and ALA-n-pentylester showed a linear correlation between logar ithm of dose and PpIX fluorescence (P < 0.005), and logarithm of dose and s kin phototoxicity with irradiation at 4.5 h (P < 0.001 and P < 0.005, respe ctively) and 6 h (P < 0.05 and P < 0.0001, respectively) after iontophoresi s. Higher phototoxicity was observed with ALA-n-pentylester than with ALA w hen sites were irradiated at 6 h, as indicated by the significantly lower t heoretical threshold dose for erythema (P < 0.05) and the shift of the PpIX fluorescence/phototoxicity curve towards greater skin erythema at equal Pp IX fluorescence levels. Depth of PpIX fluorescence in skin, as determined b y fluorescence microscopy, was similar for both prodrugs, but a more homoge neous distribution of PpIX was seen with the more lipophilic ALA-n-pentyles ter. Conclusions The observed greater phototoxicity of ALA-n-pentylester relativ e to ALA may be attributable to a more favourable PpIX localization in tiss ue and/or greater intrinsic toxicity.