title: Iontophoretic delivery of ALA provides a quantitative model for ALA pharmacokinetics and PpIX phototoxicity in human skin.
abstract: Photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) is increasingly employed for skin cancer, yet ALA dosing is crude. Using iontophoresis, we developed a rapid and quantifiable system for topical ALA delivery, with measurement of subsequent PpIX fluorescence and phototoxicity. ALA was iontophoresed from a 2% solution into upper inner arm skin of 13 healthy volunteers. Six doses of ALA were delivered with a series of charges varying from 3-120 milliCoulombs (mC); four additional doses were given with a charge of 60 mC. Five hours post-iontophoresis, sites were irradiated with broad-band yellow-red light, the series of six ALA doses receiving 100 J/cm2, while the four identical doses received 6.25, 12.5, 25, and 50 J/cm2, respectively. Resultant erythema was measured by reflectance spectroscopy. The time course of PpIX fluorescence was ALA-dose-dependent. With charge < or = 24 mC, PpIX fluorescence peaked at 3 h and returned to zero at 9-10 h, whereas charges > 24 mC had a sustained peak at 5-10 h, falling to zero by 24 h. Pre-irradiation, PpIX fluorescence correlated with ALA dose (r = 1.0). PpIX fluorescence fell immediately post-irradiation (p < 0.0001); recovery levels at 3 h correlated with ALA dose (p < 0.0001). Delayed erythema correlated with ALA dose and irradiation dose (p < 0.0001, p < 0.01, respectively). Both PpIX fluorescence intensity pre-irradiation and fall in PpIX fluorescence post-irradiation correlated with erythema (r = 0.98). Hence, PpIX synthesis is ALA-dose-dependent, and phototoxicity can be predicted from ALA dose, irradiation dose, and photobleaching of PpIX. This reproducible system allows accurate dosimetry in topical PDT and facilitates study of ALA metabolism.
authors.affiliation: Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Harvard University, Boston, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Rhodes
authors.forename: M M
authors.initials: MM
authors.lastname: Tsoukas
authors.forename: R R
authors.initials: RR
authors.lastname: Anderson
authors.forename: N
authors.initials: N
authors.lastname: Kollias
mesh_terms: D000328:Adult; D000622:Aminolevulinic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004307:Dose-Response Relationship, Radiation; D004890:Erythema / Q000139:chemically induced; D005260:Female; D005456:Fluorescent Dyes / Q000633:toxicity; D006801:Humans; D007478:Iontophoresis; D008297:Male; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000633:toxicity*; D011524:Protoporphyrins / Q000633:toxicity*; D012867:Skin / Q000187:drug effects*; D013997:Time Factors
chemical_list: D005456:Fluorescent Dyes; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX