Metabolism, Pharmacokinetics, Tissue Distribution, and Stability Studies of the Prodrug Analog of an Anti-Hepatitis B Virus Dinucleoside Phosphorothioate

The alkoxycarbonyloxy dinucleotide prodrug Rp, Sp-2 is an orally bioavailable anti-hepatitis B virus agent. The compound is efficiently metabolized to the active dinucleoside phosphorothioate Rp, Sp-1 by human liver microsomes and S9 fraction without cytochrome P450-mediated oxidation or conjugation. The conversion of Rp, Sp-2 to Rp, Sp-1 appears to be mediated by liver esterases, occurs in a stereospecific manner, and is consistent with our earlier reported studies of serum-mediated hydrolytic conversion of Rp, Sp-2 to Rp, Sp-1. However, further metabolism of Rp, Sp-1 does not occur. The presence of a minor metabolite, the desulfurized product 10 was noted. The prodrug Rp, Sp-2 was quite stable in simulated gastric fluid, whereas the active Rp, Sp-1 had a half-life of