PERCUTANEOUS-ABSORPTION OF 2',3'-DIDEOXYINOSINE IN RATS

This study explored the topical route for administering of 2',3-'dideo xyinosine (ddI), a nucleoside analog used for treating patients with a cquired immunodeficiency syndrome. A dose of ddI (similar to 180 mg/kg ) dispersed in similar to 1 g ointment base was applied, with or witho ut occlusion, to the back of high follicular density (HFD) and low fol licular density (LFD) rats. The systemic ddI clearance was determined using a concomitant administration of an intravenous tracer dose of [H -3]ddI. At 24 hr, the experiment was terminated and skin sections at t he application site were removed. After topical application, average p lateau plasma levels of about 0.6 mu g/ml were achieved within 1 to 2 hr and maintained for 24 hr. Occlusion gave a more uniform plasma prof ile but did not increase the bioavailability. The systemic bioavailabi lity in HFD and LFD rats was about the same at 33%. In addition, a dep ot of about 16% of the dose was recovered by rinsing the application a rea and extracting the drug from the excised application site. These d ata indicate that about 50% of the dermal dose penetrated the skin bar rier in 24 hr. The similar bioavailability in the HFD and LFD rats fur ther suggests an unimportant role for the transfollicular absorption r oute for ddI. The effect of a mixture of penetration enhancers, Atone and propylene glycol (5:95), was studied in HFD rats. Coadministration of ddI with the enhancers did not increase the ddI bioavailability. H owever pretreatment and coadministration with the enhancers significan tly increased the bioavailability to 62%, which is a conservative esti mate because the plasma drug level was still at a plateau when the exp eriment was terminated at 24 hr. In summary, the transdermal bioavaila bility of ddI exceeded the 15% oral bioavailability found in previous studies by more than 3 folds and was further increased by the pretreat ment with absorption enhancers. These data indicate the topical route as an attractive administration route.