title: Comparison of the pharmacokinetics and phototoxicity of protoporphyrin IX metabolized from 5-aminolevulinic acid and two derivatives in human skin in vivo.
abstract: Our novel approach was to compare the pharmacokinetics of 5-aminolevulinic acid (ALA), ALA-n-butyl and ALA-n-hexylester induced protoporphyrin IX (PpIX), together with the phototoxicity after photodynamic therapy (PDT) in human skin in vivo, using iontophoresis as a dose-control system. A series of four increasing doses of each compound was iontophoresed into healthy skin of 10 volunteers. The kinetics of PpIX metabolism (n = 4) and the response to PDT (n = 6) performed 5 h after iontophoresis, were assessed by surface PpIX fluorescence and post-irradiation erythema. Whilst ALA-induced PpIX peaked at 7.5 h, highest PpIX fluorescence induced by ALA-n-hexylester was observed at 3-6 h and no clear peak was seen with ALA-n-butylester. With ALA-n-hexylester, more PpIX was formed after 3 (P < 0.05) and 4.5 h, than with ALA or ALA-n-butylester. All compounds showed a linear correlation between logarithm of dose and PpIX fluorescence/phototoxicity at 5 h, with R-values ranging from 0.87 to 1. In addition, the ALA-n-hexylester showed the tendency to cause greater erythema than ALA and ALA-n-butylester. Fluorescence microscopy (n = 2) showed similar PpIX distributions and penetration depths for the three drugs, although both ALA esters led to a more homogeneous PpIX localization. Hence, ALA-n-hexylester appears to have slightly more favorable characteristics for PDT than ALA or ALA-n-butylester.
authors.affiliation: Department of Medicine, University of Liverpool, UK. gerscher@liv.ac.uk
authors.forename: S
authors.initials: S
authors.lastname: Gerscher
authors.forename: J P
authors.initials: JP
authors.lastname: Connelly
authors.forename: J
authors.initials: J
authors.lastname: Griffiths
authors.forename: S B
authors.initials: SB
authors.lastname: Brown
authors.forename: A J
authors.initials: AJ
authors.lastname: MacRobert
authors.forename: G
authors.initials: G
authors.lastname: Wong
authors.forename: L E
authors.initials: LE
authors.lastname: Rhodes
mesh_terms: D000328:Adult; D000622:Aminolevulinic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D007478:Iontophoresis; D008856:Microscopy, Fluorescence; D010778:Photochemotherapy / Q000009:adverse effects; D017319:Photosensitizing Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000633:toxicity; D011524:Protoporphyrins / Q000493:pharmacokinetics* / Q000633:toxicity*; D012867:Skin / Q000378:metabolism*
chemical_list: D017319:Photosensitizing Agents; D011355:Prodrugs; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX