Didanosine ester prodrugs: synthesis, albumin binding properties and pharmacokinetic studies in rats.
Three half-ester derivatives 10-12 of 5'-O-2',3'-dideoxydidanosine (DDI, 1) have been synthesized. The compounds exhibited excellent correlation between partition coefficients LogP and relative in vitro bovine serum albumin binding. Using high-performance liquid chromatography-mass spectrometry (LC-MS), DDI (1) was quantitatively determined in rat plasma after intravenous injection of the azelaic acid monoester derivative (11) of DDI. The pharmacokinetic data obtained for DDI were consistent with literature. The pharmacokinetic profile of 11 showed no significant difference in AUC(0-360) or curve shape compared to the parent drug DDI (1). The data indicate that the prodrug was converted to DDI within minutes after administration. High relative protein binding in vitro holds a promise for validity of the concept using more stable linker bonds.
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, Blindern N-0315 Oslo, Norway.
Sverre
S
Høyem
Skjalg
S
Bruheim
Gunhild
G
Maelandsmo
Marius
M
Standal
Dag Erlend
DE
Olberg
Bjarne
B
Brudeli
Anders
A
Asberg
Jo
J
Klaveness
Pål
P
Rongved
D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood* / Q000138:chemical synthesis* / Q000378:metabolism; D002417:Cattle; D016049:Didanosine / Q000097:blood* / Q000138:chemical synthesis* / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D012710:Serum Albumin, Bovine / Q000378:metabolism
D019380:Anti-HIV Agents; D011355:Prodrugs; D012710:Serum Albumin, Bovine; D016049:Didanosine