Differentiated in vivo skin penetration of salicylic compounds in hairless rats measured by cutaneous microdialysis.
The purpose was to investigate the in vivo skin penetration of four 14C-salicylic compounds using microdialysis and to relate dermal concentrations to structural features. Furthermore, to compare two in vivo retrodialysis recovery methods for estimation of true unbound extracellular concentrations. Microdialysis probes were inserted in the dermis of hairless rats. Equimolal 14C-salicylic formulations were applied topically and dialysate sampled consecutively for 4h. True extracellular concentrations were estimated by retrodialysis by drug method (the 14C-salicylic compounds themselves) and by retrodialysis by calibrator method (3H-salicylic acid as internal standard). Probe depth was measured by ultrasound scanning. High dermal concentrations were found after application of 14C-salicylamide (low protein-binding) and the lipophilic ester 14C-butyl salicylate, which was completely hydrolysed to 14C-salicylic acid during skin diffusion. Protein binding and dissociation may explain the lower dermal concentrations of 14C-salicylic acid and 14C-diethylamine salicylate, respectively. Probe depth did not significantly influence dialysate concentrations. The two in vivo recovery correction methods did not reduce the variation in concentration-time curves. In conclusion, differentiated penetration kinetics was found ranking: 14C-salicylamide >/= 14C-butyl salicylate > 14C-salicylic acid > 14C-diethylamine salicylate. Dermal concentrations were related to structural features of the model compounds. The two correction methods performed alike; however, the calibrator method has the advantage of serving as a quality control during experiments.
Simonsen
Lene
L
LEO Pharma, Pharmaceutical Formulation, 55 Industriparken, DK-2750, Ballerup, Denmark. lene.simonsen@leo-pharma.com
Jørgensen
Aksel
A
Benfeldt
Eva
E
Groth
Lotte
L
D000279:Administration, Cutaneous; D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D017551:Microdialysis; D008954:Models, Biological; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012457:Salicylamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D012459:Salicylates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption / Q000187:drug effects*; D013997:Time Factors
D012457:Salicylamides; D012459:Salicylates; C026191:diethylamine salicylate; C031060:salicylamide; C493238:butyl salicylate