Pharmacokinetic behaviour of sublingually administered 8-methoxypsoralen for PUVA therapy

Background: Conventional oral PUVA therapy is hampered by large inter- and intraindividual variations in the bioavailability of 8-methoxypsoralen (8-M OP), caused by its low solubility in the gastrointestinal juices and large interindividual differences in hepatic metabolism rate (hepatic first pass) . Aims: New galenic formulations of 8-MOP based on solid dispersions, suspens ions, and saturated solutions containing penetration enhancers were develop ed for sublingual administration, a drug delivery route which avoids the he patic first pass metabolism. Methods: Solubility properties of 8-MOP were tested in 22 potential penetra tion enhancers and solubilizers. Following preliminary in vivo tests of 13 sublingual 8-MOP formulations, five were administered to groups of voluntee rs at a nominal dose of 0.6 mg/kg body weight: two solid dispersions based on PEG 1540 (with and without Xylitol); a solution in Labrasol(R) (glyceryl and PEG-8 caprylate/caprate), PEG 400, Transcutol(R) (ethoxydiglycol) (1:1 :1); a micronized suspension in sorbitol, water, ethanol, propylene glycol (ca. 3:1:1:5 w/v); and Oxsoralen(R) capsules. Pharmacokinetic behaviour of 8-MOP was examined in serum; samples were analysed by HPLC. Photosensitivit y was measured in seven subjects. Results: The peak of maximum 8-MOP concentration in blood was sharp, rapid and reproducible: t(max) of 8-MOP in blood averaged 23+/-3 min, independent of the particular formulation. C-max was higher when 8-MOP was presented i n dissolved form (solution and capsule formulations 85+/-29 and 85+/-35 ng/ ml, respectively) and lowest with the suspension (42+/-15 ng/ml). Photosens itivity peaked reproducibly at 45 min. post dosing. Conculsions: Sublingual PUVA therapy is suitable for patients with skin typ es I and II, in particular patients who are less suitable candidates for st andard PUVA therapy (due to hepatic, renal, or cardiac insufficiency) or wh o have experienced side effects with standard PUVA.