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.
Section on Biomedical Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
P F
PF
Torrence
J
J
Kinjo
S
S
Khamnei
N H
NH
Greig
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