JAC Advance Access originally published online on September 6, 2002
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Journal of Antimicrobial Chemotherapy (2002) 50, 583-588
© 2002 The British Society for Antimicrobial Chemotherapy
P-glycoprotein and MRP1 expression and reduced ritonavir and saquinavir accumulation in HIV-infected individuals
1 Department of Pharmacology and Therapeutics, University of Liverpool, Pharmacology Research Laboratories, 70 Pembroke Place, Liverpool; 2 Department of Sexually Transmitted Diseases, Royal Free and University College, Mortimer Market Centre, London, UK
Received 8 January 2002; returned 31 May 2002; revised 13 June 2002; accepted 25 June 2002
Objectives: Efflux transporters may play a role in lowering intracellular drug concentrations. As the HIV protease inhibitors are substrates for the efflux transporters P-glycoprotein and MRP, we wished to investigate whether differences in expression of these transporters on human lymphocytes correlated with intracellular concentrations of ritonavir and saquinavir.
Patients and methods: Drug efflux transporter expression (P-glycoprotein and MRP1) on peripheral blood mononuclear cells isolated from HIV-positive patients was investigated using flow cytometry. In addition, plasma and intracellular ritonavir and saquinavir concentrations were measured by HPLC/mass spectrometry. The ratio of intracellular:plasma drug concentration was used to quantify intracellular drug accumulation.
Results: Patients with lower MRP1 expression (<median) had a significantly higher accumulation of both ritonavir and saquinavir than those with higher MRP1 expression (P = 0.035, CI = –1.70 to –0.06 and P = 0.043, CI = –12.79 to –0.11, respectively). Ritonavir accumulation was significantly greater in patients with lower P-glycoprotein expression (<median) than in patients with higher expression (P = 0.014, CI = –1.56 to –0.14). There was no relationship between saquinavir accumulation in patients and P-glycoprotein expression (P = 0.219, CI = –5.02 to 2.40). Combining expression of P-glycoprotein and MRP1 {expression index, EI = [(P-glycoprotein – 1) + (MRP1 – 1) x 100]} resulted in a statistically significant relationship between transporter expression and intracellular accumulation of both saquinavir (r2 = 0.195, P = 0.035) and ritonavir (r2 = 0.220, P = 0.049).
Conclusion: Increased expression of P-glycoprotein and MRP1 on lymphocytes is associated with lower intracellular accumulation of saquinavir and ritonavir. These two transporters may play a role in the efflux of ritonavir and saquinavir from lymphocytes in vivo.
Keywords: P-glycoprotein, MRP, accumulation, ritonavir, saquinavir
* Corresponding author: Tel: +44-151-794-5565; Fax: +44-151-794-5656; E-mail: ermeaden{at}liverpool.ac.uk
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