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Antimicrobial Agents and Chemotherapy, 06 1995, 1259-1264, Vol 39, No. 6
Copyright © 1995 by the American Society for Microbiology. All rights reserved.

Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys

ME Hawkins, H Mitsuya, CM McCully, KS Godwin, K Murakami, DG Poplack and FM Balis
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.

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 studied in a non-human primate model. ddA was rapidly and completely deaminated to didanosine, such that didanosine concentration profiles in plasma and CSF were identical following administration of ddA and didanosine. The mean clearance of didanosine was 0.50 liters/h/kg, the terminal half- life was 1.8 h, and the CSF-to-plasma ratio was 4.8%. The disposition 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 the 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 under the CSF concentration-time curve) were comparable for ddG (12.1 microM.h) and the 6-halogenated-ddG prodrugs (18.8 microM.h for 6- chloro-ddG, 9.3 microM.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 with the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhanced penetration of the prodrug and subsequent dehalogenation to ddG.(ABSTRACT TRUNCATED AT 250 WORDS)

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