title: Topical application of 5-aminolevulinic acid and its methylester, hexylester and octylester derivatives: considerations for dosimetry in mouse skin model.
abstract: Ester derivatives of 5-aminolevulinic acid (ALA-esters) have been proposed as alternative drugs for ALA in photodynamic therapy. After topical application of creams containing ALA, ALA methylester (ALA-Me), ALA hexylester (ALA-Hex) and ALA octylester (ALA-Oct) on mouse skin, typical fluorescence excitation and emission spectra of protoporphyrin IX (PpIX) were recorded, exhibiting a similar spectral shape for all the drugs in the range of concentrations (0.5-20%) studied. The accumulation kinetics of PpIX followed nearly a similar profile for all the drug formulations. The fluorescence of PpIX peaked at around 6-12 h of continuous cream application. Nevertheless, some differences in pharmacokinetics were noticed. For ALA cream, the highest PpIX fluorescence was achieved using 20% of ALA in an ointment. Conversely, 10% of ALA-Me and ALA-Hex, but not of ALA-Oct, in the cream was more efficient (P < 0.05) than was 20%. The cream becomes rather fluid when 20% of any of these ALA-esters is used in ointment, whereas 10% and lower concentrations of ALA-esters do not significantly increase fluidity of the cream. The dependence of PpIX accumulation on the concentration of ALA and ALA-ester in the applied cream followed (P < 0.002) kinetics as described by a mathematical model based on the Michaelis-Menten equation for enzymatic processes. Under the present conditions, the PpIX amount in the skin increased by around 50% by the application of ALA-Me, ALA-Hex or ALA-Oct for 4-12 h as compared with ALA for the same period. Observations of the mice under exposure to blue light showed that after 8-24 h of continuous application of ALA, the whole mouse was fluorescent, whereas in the case of ALA-Me, ALA-Hex and ALA-Oct the fluorescence of PpIX was located only at the area of initial cream application. The amount of the active compound in the applied cream necessary to induce 90% of the maximal amount of PpIX was determined for normal mouse skin. Optimal PpIX fluorescence can be attained using around 5% ALA, 10% ALA-Me and 5% ALA-Hex creams during short application times (2-4 h). Topical application of ALA-Oct may not gain optimal PpIX accumulation for short applications (<5 h). For long application times (8-12 h), it seems that around 1% ALA, 4% ALA-Me, 6% ALA-Hex and 16% ALA-Oct can give optimal PpIX fluorescence. But for long application times and high concentrations, systemic effect of ALA applied topically on relatively large areas should be considered.
authors.affiliation: Biophysics Department, The Norwegian Radium Hospital, Oslo. asta.juzeniene@klinmed.uio.no
authors.forename: Asta
authors.initials: A
authors.lastname: Juzeniene
authors.forename: Petras
authors.initials: P
authors.lastname: Juzenas
authors.forename: Vladimir
authors.initials: V
authors.lastname: Iani
authors.forename: Johan
authors.initials: J
authors.lastname: Moan
mesh_terms: D000287:Administration, Topical; D000622:Aminolevulinic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004952:Esters; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010778:Photochemotherapy; D011524:Protoporphyrins / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D004952:Esters; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX