IN-VITRO ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS AND ANTI-HEPATITIS-B VIRUSACTIVITIES AND PHARMACOKINETIC PROPERTIES OF HETERODINUCLEOSIDE PHOSPHATES CONTAINING AZT OR DDC

In vitro activities, against human immunodeficiency virus (HIV)- and h epatitis B virus (HBV)-infected cells, of four amphiphilic heterodinuc leoside phosphates containing 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxycytidine (ddC) as antiviral monomers were evaluated. The four compounds were ocytidylyl-(3'-->5')-3'-azido-2',3'-deoxythymidin e (N-4-hxddC-AZT), N-4-palmitoyl-2'-deoxyribocytidylyl-(3'-->5')- 2',3 '-deoxythymidine (N-4-pamdC-AZT), 2'-deoxycytidylyl-(3'-->5')-2',3'-di deoxythymidine (N-4-hxddC-ddC) and ylyl-(3'-->5')-N-4-palmitoyl-2',3'- dideoxycytidine (dT-N-4-pamddC). All four dimers were active against H IV, dT-N-4-pamddC being the most active and least toxic. dT-N-4-pamddC also exhibited strong antiviral effects against a panel of eight AZT- resistant HIV strains. The ddG-containing heterodimers incorporated in liposomes additionally inhibited HBV replication by 50-80% in HepG2 2 .2.15 cells. AZT and the AZT-containing dimers were ineffective. Diffe rences in pharmacokinetic properties between the antiviral monomers an d the heterodimers were evaluated using liposomal formulations of H-3- labelled AZT heterodimers as model compounds. The cellular distributio n of AZT in H9 cells was predominantly cytoplasmic, whereas the amphil philic dimers were distributed more evenly throughout the cytoplasm, n uclear membranes and microsomes. Blood levels of the heterodimers decr eased at a rate two-to threefold slower than AZT and the areas-under-t he-curves were five-to sevenfold higher for N-4-pamdC-AZT and N-4-hxdd C-AZT, respectively. Compared to AZT, the peak levels of the dimers we re three to four times higher in blood and five to six times higher in the liver. Analysis of blood samples showed that 34% of N-4-pamdC-AZT was metabolized to AZT, whereas only 9% of N-4-hxddC-AZT released AZT Considering the antiviral potency and the favourable pharmacokinetic properties of the heterodimers, these compounds merit further explorat ion as antiviral drugs.