Intracellular Concentration of Protease Inhibitors in HIV-1--Infected Patients: Correlation with MDR-1 Gene Expression and Low Dose of Ritonavir

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Abstract
Background: Protease inhibitors (PIs) are substrates for the P-glycoprotein (P-gp/170) encoded by the multi-drug resistance gene (MDR-1). HIV infection is associated with increased expression of P-gp. The role of MDR gene overexpression in clinical pharmacokinetics is not known. Method: We determined by HPLC, at trough and peak levels, the current PI concentrations in plasma (P) and in peripheral blood mononuclear cells (PBMCs) (intracellular concentration [IC]) from 49 HIV-infected patients receiving different treatment combinations: nelfinavir ([NFV] n = 12); indinavir ([IDV] n = 10); amprenavir ([APV] n = 5); ritonavir (RTV) 100 bid/IDV 800 mg bid (n = 6); RTV 400 bid/IDV 400 mg bid (n = 3); RTV 100 bid/saquinavir (SQV) 600 mg tid (n = 9); APV 600 bid/RTV 100 mg bid (n = 4). We determined the mean ratio of intracellular/plasma PI concentration for each treatment group. The MDR-1 gene expression was determined by a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). HIV viral load was simultaneously measured. Results: 49 patients (mean age 41 ± 8.7 years; mean CD4 cell count 418 [57-972]; mean HIV RNA 2.1 ± 0.8 log10) were included in the study. Patients who overexpressed the MDR-1 gene had significantly lower trough intracellular PI levels (p = .02) or lower intracellular accumulation of PI (p = .042). Patients treated with low-dose RTV in combined regimens with detectable RTV intracellular concentration showed lack of MDR-1 gene expression (p = .01). Patients with HIV RNA < 40 copies/mL had significantly higher RTV intracellular accumulation (p = .029). Conclusion: In HIV-infected patients, IC of PI is inversely correlated with MDR-1 gene overexpression. Undetectable viral load was associated with the use of low-dose RTV, probably linked to better intracellular accumulation of the drug. Nevertheless, further investigation is needed to confirm these results.