Synthesis and pharmacokinetics of a dihydropyridine chemical delivery system for the antiimmunodeficiency virus agent dideoxycytidine.
In order to explore the possibility that a dihydropyridine/pyridinium redox chemical delivery system might enhance significantly the brain uptake of the anti-HIV agent dideoxycytidine (DDC), we prepared a DDC derivative which bore the 1,4-dihydro-1-methyl-3-pyridylcarbonyl moiety at both the cytidine exocyclic amino moiety and the sugar 5'-hydroxyl function; namely, 5',4N-bis-[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl]-2',3'- dideoxycytidine (2). In cell-free extracts of rat brain tissue, compound 2 was readily converted to free DDC by stepwise oxidation and hydrolysis of the dihydropyridyl groups. Time-dependent plasma and brain concentrations of DDC and 2 were determined following iv administration of 2 (49.3 mg/kg) to rats. Compound 2 could be detected in brain, reaching peak concentrations of 7.7 +/- 2.9 nmol/g at 15 min. Low levels of DDC also were detected with a peak concentration of 1.4 +/- 0.5 nmol/g at 240 min after injection. The brain/plasma concentration integral of compound 2 was 0.95 whereas that for DDC in brain as a ratio of combined DDC and compound 2 levels in plasma was 0.24. Despite this, brain concentrations remained low and not significantly different from those achieved following administration of DDC alone.
Torrence
P F
PF
Section on Biomedical Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Kinjo
J
J
Khamnei
S
S
Greig
N H
NH
D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004337:Drug Carriers; D006678:HIV / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D016047:Zalcitabine / Q000008:administration & dosage* / Q000494:pharmacology
D004095:Dihydropyridines; D004337:Drug Carriers; D011355:Prodrugs; C081338:5',4N-bis((1,4-dihydro-1-methyl-3-pyridinyl)carbonyl)-2',3'-dideoxycytosine; D016047:Zalcitabine; D003596:Cytosine