EXTENSIVE ABSORPTION OF 2',3'-DIDEOXYINOSINE BY INTRATRACHEAL ADMINISTRATION IN RATS

Purpose. To evaluate the intratracheal route of administration as an a lternative to oral administration for 2',3'-dideoxyinosine (ddI). Meth ods. A ddI dose (40 mg/kg/300 mu l or 6.5 mg/kg/50 mu l) was instilled into the trachea in female Fisher rats and an intravenous tracer dose (9 mu g/kg) of H-1-ddI was administered concomitantly to determine th e drug clearance. Plasma concentrations were analyzed for the rate and extent of absorption. Results. ddI was rapidly absorbed from the lung s, with a bioavailability of 63% at 40 mg/kg and 101% at 6.5 mg/kg. By comparison, our previous data showed an oral bioavailability of about 15% (Pharm Res., 9:822, 1992). The distribution of a dye solution ins tilled intratracheally showed that a fraction of the 300 mu l dose spi lled over to the gastrointestinal tract, where the entire 50 mu l dose was retained in the lungs. The different distribution of the two dose s/volumes likely contributed to the different bioavailability, with a fraction of the higher dose/volume degraded in the gastrointestinal tr act after the spillover. Absorption of ddI from the airspace of the lu ng was biexponential, suggesting two absorption processes. Conclusions . These data indicate significantly higher and less variable bioavaila bility of ddI by the intratracheal route of delivery compared to the o ral route. Furthermore, the complete bioavailability at the lower dose /volume indicates no significant pulmonary first pass elimination for ddI.