DETERMINATION OF ACITRETIN IN THE SKIN, IN THE SUCTION BLISTER, AND IN PLASMA OF HUMAN VOLUNTEERS AFTER MULTIPLE ORAL DOSING

Several HPLC methods for quantification of acitretin and its 13-cis is omer in biological fluids have been described. Only limited data are a vailable on determination of this drug in skin samples. Our objective was to improve the sensitivity and selectivity of existing methods to measure drug in small skin samples from humans treated with acitretin. With a new optimized mobile phase [methanol: acetonitrile (7:3, v/v), purified water with 1.5 % (v/v) acetic acid, mixed in a 85:15 ratio ( v/v)] and a new internal standard (arotinoid ethyl sulfone), a limit o f quantification of 1 ng/g tissue was reached. Nine male volunteers we re given an oral daily dose of 50 mg acitretin for up to 28 days. Bloo d and skin samples (punch and shave biopsies, suction blister skin, an d fluid) were taken at various time points during and after treatment. Drug concentration and metabolism in plasma and skin samples appeared to be linked in that the trans-isomer concentration was always higher than the cis-isomer concentration during dosing and 3 h after the las t dose. However, 7 and 14 days after the last dose in plasma and in al l tissue samples (except the shave biopsy), the all-trans-acitretin co ncentration rapidly decreased and approached the detection limit. In t he shave biopsy, the all-trans-acitretin concentration remained higher than the 13-cis-acitretin concentration. Furthermore, the elimination of two isomers from the shave biopsy was delayed. Our HPLC method has provided a suitable tool for pharmacokinetic and drug monitoring stud ies of all-trans-acitretin and 13-cis-acitretin that can be performed by any laboratory with a darkroom and a basic isocratic HPLC system.