Genetic Variation of Kinases and Activation of Nucleotide Analog Reverse Transcriptase Inhibitor Tenofovir

Abstract

As antiretroviral therapy has become more accessible across the world and coformulations have improved patient compliance; the morbidity and mortality of HIV/AIDS has decreased. However, there is still a substantial gap in knowledge regarding the impact of genetic variation on the metabolism of and response to some of the most commonly prescribed antiretrovirals, including the nucleotide reverse transcriptase inhibitor tenofovir. While it has been scientifically established that tenofovir must be activated to be efficacious against HIV, the enzymes responsible for this activation have not been well characterized. The purpose of this review is to summarize and clarify the scientific knowledge regarding the enzymes that phosphorylate and activate this clinically important drug.

Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques

“…Modeling an increase in the phosphorylation rates ( k f1 and/or k f2 ) coupled with changes in lymphocytes trafficking rates as result of ART-induced reduction in immune activation ( 55 ) led to an increase in IADM levels in both LNMC and PBMC, with a steeper growth in the former compartment, as observed in our dataset. This hypothesis would not conflict with the observation that endogenous dNTP concentrations were not statistically significantly different between M1 and M3 because different (or a subset of) kinases with widely differing affinities for their unphosphorylated substrates could be responsible for the formation of active drug-metabolities vs. endogenous nucleotides; indeed, enzymes that could potentially phosphorylate TFV are still under investigation ( 56 ). In this scenario, the simulations also predict an accumulation of several-fold higher parent drug levels in the LNs than in the plasma and a plateau reached by month 1 of ART, which appears consistent with the dynamics of parent TFV in LNs found in a subgroup of animals for which this covariate was observed (Subgroup A).…”

An open-label, randomized, single intravenous dosing study to investigate the effect of fixed-dose combinations of tenofovir/lamivudine or atazanavir/ritonavir on the pharmacokinetics of remdesivir in Ugandan healthy volunteers (RemTLAR)

“…Potential for genetic variation exists among kinases (adenylate kinase 2 (AK2) creatine kinase, muscle (CKM) pyruvate kinase, muscle (PKM) and pyruvate kinase, liver, and red blood cell (PKLR)) responsible for intracellular phosphorylation of tenofovir [ 17 ]. Known polymorphisms considered likely to alter intracellular exposure of tenofovir will be described [ 18 ].…”

Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

“…The identities of kinases for the phosphorylation remain to be determined. Several kinases, such as adenylate kinase 2, pyruvate kinases, and thymidine kinase 1, have nevertheless been implicated in such catalytic actions toward nucleoside analog drugs such as tenofovir 113 . These kinases have a broad tissue distribution, but a majority of them are expressed in cell‐ and organ‐specific manner.…”

“…Several kinases, such as adenylate kinase 2, pyruvate kinases, and thymidine kinase 1, have nevertheless been implicated in such catalytic actions toward nucleoside analog drugs such as tenofovir. 113 These kinases have a broad tissue distribution, but a majority of them are expressed in cell-and organspecific manner. The metabolic fate of these phosphorylated metabolites remains largely unknown.…”