Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors

The inclusion of HIV protease inhibitor (PI) drugs in so-called 'highly active antiretroviral therapy' (HAART) has substantially improved the clinical perspectives for HIV-infected individuals, but full eradication of HIV infection is still an unachieved goal. One of the factors that may limit the therapeutic efficacy of PIs is the activity of P-glycoprotein (P-gp). This plasma membrane localized drug transporter can actively extrude the currently used PIs from cells. P-gp is not only present in a subfraction of lymphocytes, one of the main targets of HIV, but also in a range of pharmacological barriers that could give rise to potential HIV sanctuary sites in the body, such as brain and testis. Moreover, PI oral bioavailability and penetration into the foetus also appears to be hindered by P-gp activity. P-gp may therefore limit the penetration of the PI into several therapeutically relevant compartments, and thus diminish the chance of achieving a curative treatment regimen. This review focuses on current insights into the pharmacological role of P-gp for PI disposition, and on potential strategies to interfere with P-gp function that could lead to an improvement of current HIV pharmacotherapy.