Cellular nucleoside pharmacokinetics and pharmacology: a potentially important determinant of antiretroviral efficacy

Abstract

Among the potential reasons for treatment failure in patients receiving therapy for HIV-1 infection, one that has received only limited attention is intracellular interactions between nucleosides that may reduce their metabolism (phosphorylation) to active forms necessary for antiretroviral activity. Results reviewed in this paper indicate that there is considerable potential for interaction among nucleosides used to suppress viral replication in patients with HIV-1 infection. Zidovudine (ZDV) and zalcitabine (ddC) have both been shown to inhibit their own metabolism. ZDV also inhibits the phosphorylation of stavudine (d4T) and lamivudine (3TC) and increases that of didanosine (ddI). d4T has been shown to slightly decrease the phosphorylation of ZDV. ddC decreases the formation of triphosphates of both d4T and 3TC, and 3TC decreases the phosphorylation of ddC. ddI has no significant effects on the intracellular metabolism of any of the nucleoside analogues currently used to treat patients with HIV-1 disease. Thus, the pharmacokinetics of antiretroviral agents and intracellular phosphorylation/activation of nucleosides may be important determinants of the virologic and clinical effectiveness of therapy. They must be considered along with characteristics of the virus, such as phenotypic and genotypic resistance, and those of the patient, including motivation to adhere to therapy, in individualizing antiretroviral treatment regimens for individuals with HIV-1 disease.