Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-d-Dioxolane)Thymine in Rhesus Monkeys

Abstract

The discovery of the antiviral activity of ␤-D-dioxolaneguanine (DXG) and its prodrug amdoxovir (DAPD) against zidovudine (AZT)-and lamivudine-resistant mutants (19) prompted us to revisit D-DOT to explore the activity against mutant viruses, since D-DOT also contains the dioxolane sugar moiety (see Fig. 1). D-DOT demonstrated potent activity in human PBM cells against lamivudine-resistant (M184V) (EC 50 ϭ 0.088 to 0.2 M), tenofovir-resistant (K65R) (EC 50 ϭ 0.21 M), didanosine-resistant (L74V) (EC 50 ϭ 0.33 M), and zidovudine-resistant (thymidine analog mutations) (EC 50 ϭ 0.49 M) viruses (13,15,16). D-DOT-triphosphate also demonstrated activity against wild-type HIV-1 reverse transcriptase and reverse transcriptases of various mutants, including those of thymidine analog mutants and the M184V mutant, in an enzymatic study (27). The activity of dioxolane nucleoside triphosphate against many resistant HIV-1 strains may be due to reduced steric hindrance at the active site and to a specific interaction of the 3Ј-oxygen atom with nearby enzyme through H bonding (13,15,16). D-DOT, like AZT and 3Ј-deoxy-2Ј,3Ј-didehydrothymidine (stavudine [D4T]), is also a thymidine analogue that requires cellular TK for activation. The toxicities of AZT and D4T in humans undergoing treatment with these drugs are well known despite their usefulness in drug cocktails (1,23,33,36,37,42). Therefore, there is a need to develop TK-dependent nucleoside analogues with limited toxicities that could provide additional treatment options.The objective of this study was to assess the single-dose pharmacokinetics (PK) of D-DOT in rhesus monkeys given 33.3-mg/kg-of-body-weight intravenous and oral doses and to compare the pharmacokinetics with those of other structurally related antiretroviral nucleoside analogs that were previously administered to rhesus monkeys (7,8,10,11,12,24,28,30,34,39). MATERIALS AND METHODS Chemicals.The synthesis of D-DOT (molecular weight ϭ 228.2) (Fig. 1) and the internal standard, AZT, has been described elsewhere (14,26). The chemical purity of each compound was found to be greater than 98% using high-performance liquid chromatography (HPLC) and spectral analysis. Acetonitrile

Pre‐clinical pharmacological profile of QF‐036, a potent HIV‐1 maturation inhibitor

“…Understanding the pharmacokinetic profile of a drug is important for estimating the rate and extent of absorption and elimination 18‐21 . Of particular significance are data associated with drug exposure, drug half‐life, systemic distribution and clearance.…”

“…Understanding the pharmacokinetic profile of a drug is important for estimating the rate and extent of absorption and elimination. [18][19][20][21] Of particular significance are data associated with drug exposure, drug half-life, systemic distribution and clearance. Moreover, in vitro ADM data provide additional information for the analysis and interpretation of in vivo data.…”

A Review of the Ongoing Research on Zika Virus Treatment

“…In the search for effective antivirals, research centers have screened compounds which previously demonstrated to possess antiviral activity against other pathogens for their therapeutical potential against ZIKV infection [ 40 ]. As an example, nucleoside analogues showed to inhibit the viral replication of the herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) [ 80 ], cytomegalovirus (CMV) [ 81 ], hepatitis B virus (HBV) [ 82 ], human immunodeficiency virus (HIV) [ 83 , 84 , 85 , 86 ], and hepatitis C virus [ 87 ].…”