This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.b-D-Dioxolane-2,6-diaminopurine (DAPD) is the prodrug of b-D-dioxolane guanosine (DXG) that is readily converted into DXG by the ubiquitous enzyme adenosine deaminase. DXG has potent, selective in vitro activity against several clinically important resistant HIV mutants and is in advanced preclinical development. Average oral bioavailability of DAPD/DXG after DAPD oral administration was only 30% in rhesus monkeys. Valyl-(-)-b-D-2,6-diaminopurine dioxolane (Val-DAPD), a prodrug of DAPD was synthesized in an effort to improve oral bioavailability. Single dose oral pharmacokinetics of Val-DAPD was studied in 3 rhesus monkeys. Urine and serum samples were collected after dosing at 8 and 24 h, respectively. Cerebrospinal fluid (CSF) samples were collected at 1, 2 and 3 h. A non-compartmental pharmacokinetic analysis was performed to the serum data using a non-linear regression curve-fitting program (WinNonlin). A large variation in the pharmacokinetic (PK) parameters was found in the monkeys following 33.3 mg/kg val-DAPD oral administration. Peak serum concentrations were achieved between 0.25 to 3 h (Tmax) after dosing. Terminal half-lives for DXG were between 0.58 to 2.83 h. Volumes of distribution/F ranged from 2.37 to 16.33 l/kg; the average oral systemic clearance/F value was 7.9 l/kg/h. DXG was found in the CSF samples except in one monkey due to the time-lag (tlag) of 2 h and 3 h samples not collected from this animal. Three, 11 and 23% of the administered dose was recovered in the form of DAPD and 14, 19 and 35% was recovered in the form of DXG in the urine, within 8 h of administration. A total of 17, 30, and 58% of the administered dose were eliminated within 8 h in the urine, suggesting that the prodrug was rapidly hydrolyzed into DAPD and gave reasonably high levels of DXG in two animals. Very low absorption was noted in one animal. Further work is needed to identify sources of inter-individual pharmacokinetic variability.
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