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

This study explored the topical route for administering of 2',3-'dideoxyinosine (ddI), a nucleoside analog used for treating patients with acquired immunodeficiency syndrome. A dose of ddI (similar to 180 mg/kg) dispersed in similar to 1 g ointment base was applied, with or without occlusion, to the back of high follicular density (HFD) and low follicular 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 the application site were removed. After topical application, average plateau 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 profile but did not increase the bioavailability. The systemic bioavailability in HFD and LFD rats was about the same at 33%. In addition, a depot of about 16% of the dose was recovered by rinsing the application area and extracting the drug from the excised application site. These data indicate that about 50% of the dermal dose penetrated the skin barrier in 24 hr. The similar bioavailability in the HFD and LFD rats further suggests an unimportant role for the transfollicular absorption route 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. However pretreatment and coadministration with the enhancers significantly increased the bioavailability to 62%, which is a conservative estimate because the plasma drug level was still at a plateau when the experiment was terminated at 24 hr. In summary, the transdermal bioavailability of ddI exceeded the 15% oral bioavailability found in previous studies by more than 3 folds and was further increased by the pretreatment with absorption enhancers. These data indicate the topical route as an attractive administration route.