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In Vitro Anti-Human Immunodeficiency Virus And Anti-Hepatitis B Virus Activities And Pharmacokinetic Properties Of Heterodinucleoside Phosphates Containing AZT Or DdC

PA Peghini, R Zahner, H Kuster, H Schott, RA Schwendener

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In vitro activities, against human immunodeficiency virus (HIV)- and hepatitis B virus (HBV)-infected cells, of four amphiphilic heterodinucleoside phosphates containing 3′-azido-2′,3′-dideoxythymidine (AZT) or 2′,3′-dideoxycytidine (ddC) as antiviral monomers were evaluated. The four compounds were N4-hexadecyl-2′-deoxyribocytidylyl-(3′→5′)-3′-azido-2′,3′-deoxythymidine (N4-hxddC-AZT), N4-palmitoyl-2′-deoxyribocytidylyl-(3′→5′)-3′-azido-2′,3′-deoxythymidine (N4-pamdC-AZT), N4-hexadecyl-2′-deoxycytidylyl-(3′→5′)-2′,3′-dideoxycytidine (N4-hxddC-ddC) and 2′-deoxythymidylyl-(3′→5′)-N4-palmitoyl-2′,3′-dideoxycytidine (dT-N4-pamddC). All four dimers were active against HIV, dT-N4-pamddC being the most active and least toxic. dT-N4-pamddC also exhibited strong antiviral effects against a panel of eight AZT-resistant HIV strains. The ddC-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. Differences in pharmacokinetic properties between the antiviral monomers and the heterodimers were evaluated using liposomal formulations of3H-labelled AZT heterodimers as model compounds. The cellular distribution of AZT in H9 cells was predominantly cytoplasmic, whereas the amphiphilic dimers were distributed more evenly throughout the cytoplasm, nuclear membranes and microsomes. Blood levels of the heterodimers decreased at a rate two- to threefold slower than AZT and the areas-under-the-curves were five- to sevenfold higher for N4-pamdC-AZT and N4-hxddC-AZT, respectively. Compared to AZT, the peak levels of the dimers were three to four times higher in blood and five to six times higher in the liver. Analysis of blood samples showed that 34% of N4-pamdC-AZT was metabolized to AZT, whereas only 9% of N4-hxddC-AZT released AZT. Considering the antiviral potency and the favourable pharmacokinetic properties of the heterodimers, these compounds merit further exploration as antiviral drugs.