Intracellular pharmacology of nucleoside analogues and protease inhibitors: role of transporter molecules.

Antiretroviral agents target HIV replication within infected cells. It is therefore important to focus on the pharmacology of these drugs at their site of action rather than just in plasma. Activation of nucleoside analogues to a triphosphate is essential for antiretroviral activity. Following activation, by intracellular kinases, drug triphosphates compete with endogenous triphosphates for HIV reverse transcriptase. Methodologies to measure triphosphates in peripheral blood mononuclear cells from HIV patients have been described. This has allowed investigation of once-daily dosing regimens, drug interactions, modulation of intracellular activation and the bypassing of initial phosphorylation steps. Drug accumulation within a cell is a balance between influx and efflux. There is a growing body of evidence indicating that transport proteins are vitally important in regulating intracellular concentrations of antiretroviral drugs. Allelic variants, inhibition (or induction) are all potentially critical determinants of active drug present in the cell. It is hoped that understanding the intracellular pharmacology will improve long-term therapy and reduce the likelihood of cellular resistance in therapeutic failure.