Short communication cellular pharmacology of 9-(beta-D-1,3-dioxolan-4-yl) guanine and its lack of drug interactions with zidovudine in primary human lymphocytes.
Amdoxovir, currently in Phase II clinical trials, is rapidly converted to 9-(beta-D-1,3-dioxolan-4-yl)guanine (DXG) by adenosine deaminase in vitro and in humans. The cellular pharmacology of DXG in primary human lymphocytes, including dose-response relationships, intracellular half-life of DXG triphosphate (DXG-TP), and combination studies were determined. DXG produced high levels of DXG-TP with a long half-life (16 h) in activated human peripheral blood mononuclear cells. Since zidovudine (ZDV) and DXG select for different resistance mutations, co-formulation of the these two drugs is an attractive proposition. A combination study between DXG and ZDV showed no reduction of DXG-TP or ZDV-TP. Taken together, these results suggest that an appropriately designed DXG prodrug could be given once a day and that co-formulation with ZDV might be a possibility.
Hernandez-Santiago
Brenda I
BI
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Veterans Affairs Medical Center, Decatur, GA 30033, USA.
Obikhod
Aleksandr
A
Fromentin
Emilie
E
Hurwitz
Selwyn J
SJ
Schinazi
Raymond F
RF
D002478:Cells, Cultured; D004148:Dioxolanes / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000821:virology; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011355:Prodrugs / Q000494:pharmacology; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology*
C108472:9-(1,3-dioxolan-4-yl)guanine; D004148:Dioxolanes; D011355:Prodrugs; D015215:Zidovudine; D006147:Guanine