PHARMACOKINETICS OF DIDEOXYPURINE NUCLEOSIDE ANALOGS IN PLASMA AND CEREBROSPINAL-FLUID OF RHESUS-MONKEYS

The pharmacokinetics of 2',3'-dideoxyadenosine (ddA), didanosine, 2',3 '-dideoxyguanosine (ddG), and 6-halogenated prodrugs of ddG, 6-chloro- ddG and 6-iodo-ddG, in plasma and cerebrospinal fluid (CSF) were studi ed in a non-human primate model, ddA was rapidly and completely deamin ated to didanosine, such that didanosine concentration profiles in pla sma and CSF were identical following administration of ddA and didanos ine, The mean clearance of didanosine was 0.50 liters/h/kg, the termin al half-life was 1.8 h, and the CSF-to-plasma ratio was 4.8%, The disp osition of ddG was similar, with a clearance of 0.70 liters/h/kg and a half-life of 1.7 h, The adenosine deaminase-mediated conversion of th e 6-halogenated-ddG prodrugs to ddG was rapid but incomplete (48% for 6-chloro-ddG and 29% for 6-iodo-ddG), The CSF-to-plasma ratios of ddG with equimolar doses of ddG, 6-chloro-ddG, and 6-iodo-ddG were 8.5, 24 , and 17%, respectively, but the actual ddG exposures in CSF (area und er the CSF concentration-time curve) were comparable for ddG (12.1 mu M . h) and the 6-halogenated-ddG prodrugs (18.8 mu M . h for 6 chloro- ddG, 9.3 mu M . h for 6-iodo-ddG), 6-Chloro-ddG was not detectable in plasma or CSF, and the CSF-to-plasma ratio of 6-iodo-ddG was 9.4%, so the higher CSF-to-plasma ratios of ddG,vith the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhance d penetration of the prodrug and subsequent dehalogenation to ddG, The penetration of ddG into CSF exceeds that of didanosine and is enhance d by administration of the 6-halogenated prodrugs, although the mechan ism of this enhanced penetration is unclear.