DIRECT TRANSPORT OF 2',3'-DIDEHYDRO-3'-DEOXYTHYMIDINE (D4T) AND ITS ESTER DERIVATIVES TO THE CEREBROSPINAL-FLUID VIA THE NASAL MUCOUS-MEMBRANE IN RATS

We investigated the absorption and transport of 2',3'-didehydro-3'-deo xythymidine (D4T) and its ester prodrugs from the nasal cavity in rats . The absorption of D4T and its acetate (C2-D4T) was rapid and almost complete. although the hemi-succinate (Suc-D4T) was absorbed rather sl owly; the plasma concentrations of the prodrug, Suc-D4T, and regenerat ed D4T remained unchanged throughout the experimental period (180 min) . Concentrations in the cerebrospinal fluid (CSF) following intravenou s (i.v.) and intranasal (i.n.) administration mere also measured. Afte r i.n. administration, drug concentrations were higher in the fraction derived from the subarachnoid space located close to the nasal mucosa than those in the fractions located far from the nasal cavity. This d ifference was not found following the i.v. administration of the drugs . Following nasal administration, the intact Suc-D4T was found in the CSF at a concentration higher than that of D4T, although transport of the intact prodrug to the CSF was not observed following i.v. administ ration. These results suggest that direct transport of the drugs from the nasal cavity to the CSF significantly contributes to the higher co ncentrations in CSF of D4T and/or its ester prodrugs, and indicate the possible value of nasal administration for the treatment of patients with AIDS dementia.