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Metabolism of Tenofovir and Didanosine in Quiescent or Stimulated Human Peripheral Blood Mononuclear Cells
Author(s) -
Robbins Brian L.,
Wilcox Carrie K.,
Fridland Arnold,
Rodman John H.
Publication year - 2003
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1592/phco.23.6.695.32189
Subject(s) - didanosine , peripheral blood mononuclear cell , tenofovir , pharmacology , reverse transcriptase inhibitor , chemistry , in vitro , biology , virology , virus , biochemistry , human immunodeficiency virus (hiv) , viral disease , sida
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 μ didanosine to dideoxyadenosine triphosphate (ddATP) was determined in quiescent and stimulated PBMCs in the presence or absence of 5 μ tenofovir. Similarly, phosphorylation of 5 μ tenofovir to tenofovir diphosphate (TFV pp ) was examined in the presence or absence of 2 and 20 μ didanosine. Intracellular amounts of ddATP and TFV pp 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 μ didanosine. In addition, didanosine did not alter the amount of TFV pp 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 TFV pp 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.