Azidothymidine homodinucleotide-loaded erythrocytes and bioreactors for slow delivery of the antiretroviral drug azidothymidine.
A new Azidothymidine derivative, di-(thymidine-3'- azido-2',3'-dideoxy-D-riboside)-5'-5'-p1-p2-pyrophosphate (AZTp2AZT), was encapsulated in human erythrocytes according to a conservative procedure of hypotonic shock-isotonic resealing and reannealing. Like in erythrocyte lysates supplemented with 1 mM ATP, intact red cells too were found to convert AZTp2AZT to 3'-Azido-3'-deoxythymidine which was then released linearly in plasma. The major metabolic pathway involved in this conversion was the symmetrical hydrolysis of AZTp2AZT to yield two 3'-Azido-3'- deoxythymidine-5'-phosphate molecules which were then dephosphorylated to 3'-Azido-3'-deoxythymidine. At late times of incubation, also a limited asymmetrical hydrolysis of AZTp2AZT became apparent in the intact erythrocytes, yielding 3'-Azido-3'-deoxythymidine-5'-diphosphate that was then converted to the triphosphorylated derivative. Therefore, erythrocytes loaded with AZTp2AZT act "in vitro" as bioreactors ensuring sustained and potentially useful release of 3'-Azido-3'-deoxythymidine.
Benatti
U
U
Institute of Biochemistry, University of Genoa, Italy.
Giovine
M
M
Damonte
G
G
Gasparini
A
A
Scarfi
S
S
De Flora
A
A
Fraternale
A
A
Rossi
L
L
Magnani
M
M
D054306:Dideoxynucleotides; D004337:Drug Carriers; D004912:Erythrocytes / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D066298:In Vitro Techniques; D011355:Prodrugs / Q000008:administration & dosage* / Q000378:metabolism; D013942:Thymine Nucleotides / Q000008:administration & dosage* / Q000378:metabolism; D015215:Zidovudine / Q000008:administration & dosage* / Q000378:metabolism / Q000031:analogs & derivatives
D054306:Dideoxynucleotides; D004337:Drug Carriers; D011355:Prodrugs; D013942:Thymine Nucleotides; C098899:azidothymidine homodinucleotide; D015215:Zidovudine