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Vol. 56, Issue 4, 693-704, October 1999
Rega Institute for Medical Research, Katholieke Universiteit
Leuven, Leuven, Belgium (D.S., L.N., E. De C., J.B.); and Welsh School
of Pharmacy, University of Wales, Cardiff, United Kingdom (D.C., A.S.,
R.P., S.V., C.M.)
The phosphoramidate triester prodrugs of anti-human HIV
2',3'-dideoxynucleoside analogs (ddN) represent a convenient approach to bypass the first phosphorylation to ddN 5'-monophosphate (ddNMP), resulting in an improved formation of ddN 5'-triphosphate and, hence,
higher antiviral efficacy. Although phosphoramidate derivatization markedly increases the anti-HIV activity of
2',3'-didehydro-2',3'-dideoxythymidine (d4T) in both wild-type and
thymidine kinase-deficient CEM cells, the concept is far less
successful for the 3'-azido-2',3'-dideoxythymidine (AZT) triesters. We
now investigated the metabolism of triester prodrugs of d4T and AZT
using pure enzymes or different biological media. The efficiency of the
first activation step, mediated by carboxylesterases, consists of the
formation of the amino acyl ddNMP metabolite. The efficiency of this
step was shown to be dependent on the amino acid, alkyl ester, and ddN
moiety. Triesters that showed no conversion to the amino acyl ddNMP
accumulated as the phenyl-containing intermediate and had poor, if any,
anti-HIV activity. In contrast to the relative stability of the
triesters in human serum, carboxylesterase-mediated cleavage of the
prodrugs was found to be remarkably high in mouse serum. The subsequent conversion of the amino acyl ddNMP metabolite to ddNMP or ddN was
highest in rat liver cytosolic enzyme preparations. Although L-alaninyl-d4TMP was efficiently converted to d4TMP, the
main metabolite formed from L-alaninyl-AZTMP was the free
nucleoside (AZT), thus explaining why d4T prodrugs, but not AZT
prodrugs, retain anti-HIV activity in HIV-infected thymidine
kinase-deficient cell cultures. The rat liver phosphoramidase
responsible for the formation of ddNMP was shown to be distinct from
creatine kinase, alkaline phosphatase, and phosphodiesterase.
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