Metabolism of Tenofovir and Didanosine
Objective: As tenofovir disoproxil fumarate substantially increases plasma concentrations of didanosine in patients with human immunodeficiency virus-1 infection, we sought to determine whether tenofovir and didanosine showed a similar intracellular interaction in human peripheral blood mononuclear cells (PBMCs).
Design: Comparative in vitro incubation of two antiretrovirals in lymphocytes.
Setting. Clinical research laboratory.
Material: Radiolabeled tenofovir and didanosine in human PBMCs.
Measurements and Main Results: Phosphorylation of 2 and 20 µM didanosine to dideoxyadenosine triphosphate (ddATP) was determined in quiescent and stimulated PBMCs in the presence or absence of 5 µM tenofovir. Similarly, phosphorylation of 5 µM tenofovir to tenofovir diphosphate (TFVpp) was examined in the presence or absence of 2 and 20 µM didanosine. Intracellular amounts of ddATP and TFVpp were determined by incubating PBMCs with radiolabeled tenofovir or didanosine alone and together for up to 16 hours and then separating the anabolites by high-performance liquid chromatography for quantitation. The presence of tenofovir did not affect the amount of ddATP in quiescent or stimulated PBMCs with 2 or 20 µM didanosine. In addition, didanosine did not alter the amount of TFVpp that formed. The amount of ddATP was modestly (1.5-3-fold) but consistently higher in stimulated than in quiescent PBMCs, but the amount of TFVpp did not differ.
Conclusion: There is no significant interaction between tenofovir and didanosine in human PBMCs as determined by the extent of formation of the phosphorylated anabolites. This suggests that adjusting didanosine dosage, when given with tenofovir, to achieve similar didanosine plasma concentrations, may be sufficient to accommodate the systemic drug interaction.
Tenofovir disoproxil fumarate (tenofovir DF) is an acyclic phosphonate analog of adenosine recently approved for treatment of human immunodeficiency virus (HIV)-1 infection. It is highly active when given as part of a combination antiretroviral regimen for previously treated or therapy-naïve patients infected with HIV-1. Didanosine is a purine analog nucleoside reverse transcriptase inhibitor administered in combination with other antiretroviral agents. Both the buffered tablet and enteric-coated formulations of didanosine can be administered once/day, making coadministration with tenofovir DF an attractive option for patients.
Recent reports have shown that when these two agents are administered together, plasma concentrations of didanosine are higher than when didanosine is given alone. When healthy subjects who were HIV-1 negative were given didanosine buffered tablets or the enteric-coated formulation at times separate from tenofovir DF administration, the didanosine mean area under plasma concentration-time curve (AUC) was increased 46% and 48%, respectively compared with didanosine given alone. Tenofovir DF did not alter renal clearance of didanosine, and no effects of didanosine on the pharmacokinetic parameters of tenofovir were noted. One plausible explanation for the interaction between these agents is an increase in the fraction of didanosine absorbed as a consequence of tenofovir altering gastrointestinal transport or metabolism given the lack of an effect of tenofovir on the renal clearance of didanosine.
The antiviral activity of nucleoside and nucleotide analogs is dependent on the intracellular phosphorylation of the parent compound to form active anabolites in lymphocytes. Although intracellular phosphorylated anabolites can be measured in the peripheral blood mononuclear cells (PBMCs) of patients receiving other nucleosides, such as zidovudine and lamivudine, similar analytical methods have only recently become available for measuring didanosine and are not yet available for tenofovir. To determine whether the intracellular metabolism of tenofovir, didanosine, or both is altered in addition to the demonstrated systemic drug interaction, we examined the phosphorylation of these agents in human PBMCs. The concentrations of agents were similar to those achieved in the plasma of patients receiving currently recommended dosages of each agent for treatment of HIV-1 infection.
Objective: As tenofovir disoproxil fumarate substantially increases plasma concentrations of didanosine in patients with human immunodeficiency virus-1 infection, we sought to determine whether tenofovir and didanosine showed a similar intracellular interaction in human peripheral blood mononuclear cells (PBMCs).
Design: Comparative in vitro incubation of two antiretrovirals in lymphocytes.
Setting. Clinical research laboratory.
Material: Radiolabeled tenofovir and didanosine in human PBMCs.
Measurements and Main Results: Phosphorylation of 2 and 20 µM didanosine to dideoxyadenosine triphosphate (ddATP) was determined in quiescent and stimulated PBMCs in the presence or absence of 5 µM tenofovir. Similarly, phosphorylation of 5 µM tenofovir to tenofovir diphosphate (TFVpp) was examined in the presence or absence of 2 and 20 µM didanosine. Intracellular amounts of ddATP and TFVpp were determined by incubating PBMCs with radiolabeled tenofovir or didanosine alone and together for up to 16 hours and then separating the anabolites by high-performance liquid chromatography for quantitation. The presence of tenofovir did not affect the amount of ddATP in quiescent or stimulated PBMCs with 2 or 20 µM didanosine. In addition, didanosine did not alter the amount of TFVpp that formed. The amount of ddATP was modestly (1.5-3-fold) but consistently higher in stimulated than in quiescent PBMCs, but the amount of TFVpp did not differ.
Conclusion: There is no significant interaction between tenofovir and didanosine in human PBMCs as determined by the extent of formation of the phosphorylated anabolites. This suggests that adjusting didanosine dosage, when given with tenofovir, to achieve similar didanosine plasma concentrations, may be sufficient to accommodate the systemic drug interaction.
Tenofovir disoproxil fumarate (tenofovir DF) is an acyclic phosphonate analog of adenosine recently approved for treatment of human immunodeficiency virus (HIV)-1 infection. It is highly active when given as part of a combination antiretroviral regimen for previously treated or therapy-naïve patients infected with HIV-1. Didanosine is a purine analog nucleoside reverse transcriptase inhibitor administered in combination with other antiretroviral agents. Both the buffered tablet and enteric-coated formulations of didanosine can be administered once/day, making coadministration with tenofovir DF an attractive option for patients.
Recent reports have shown that when these two agents are administered together, plasma concentrations of didanosine are higher than when didanosine is given alone. When healthy subjects who were HIV-1 negative were given didanosine buffered tablets or the enteric-coated formulation at times separate from tenofovir DF administration, the didanosine mean area under plasma concentration-time curve (AUC) was increased 46% and 48%, respectively compared with didanosine given alone. Tenofovir DF did not alter renal clearance of didanosine, and no effects of didanosine on the pharmacokinetic parameters of tenofovir were noted. One plausible explanation for the interaction between these agents is an increase in the fraction of didanosine absorbed as a consequence of tenofovir altering gastrointestinal transport or metabolism given the lack of an effect of tenofovir on the renal clearance of didanosine.
The antiviral activity of nucleoside and nucleotide analogs is dependent on the intracellular phosphorylation of the parent compound to form active anabolites in lymphocytes. Although intracellular phosphorylated anabolites can be measured in the peripheral blood mononuclear cells (PBMCs) of patients receiving other nucleosides, such as zidovudine and lamivudine, similar analytical methods have only recently become available for measuring didanosine and are not yet available for tenofovir. To determine whether the intracellular metabolism of tenofovir, didanosine, or both is altered in addition to the demonstrated systemic drug interaction, we examined the phosphorylation of these agents in human PBMCs. The concentrations of agents were similar to those achieved in the plasma of patients receiving currently recommended dosages of each agent for treatment of HIV-1 infection.
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