127. Reduced Accumulation of Ritonavir and Saquinavir in PBMCs <i>in Vivo</i> is Associated with Increased P-gp and MRP1 Expression in HIV-Infected Individuals

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Session 28 Oral Abstract Session
Pharmacology of Antiretroviral Chemotherapeutic Agents: Pharmacokinetics and Therapeutic Drug Monitoring
Session Time: Wednesday, 11:15 am - 12:30 pm
Room 6E

11:30 127.

Reduced Accumulation of Ritonavir and Saquinavir in PBMCs in Vivo is Associated with Increased P-gp and MRP1 Expression in HIV-Infected Individuals
E. Meaden*¹, P. Hoggard¹, P. Newton², J. F. Tjia¹, D. Aldam², D. Cornforth², J. Lloyd¹, A. Smith², I. Williams², N. Beeching³, E. Stockwell⁴, E. Wilkins⁴, P. Carey⁵, D. Back¹, and S. Khoo¹
¹Univ. of Liverpool; ²Mortimer Market Centre, London; ³Univ. Hosp. Aintree, Liverpool; ⁴North Manchester Gen. Hosp; and ⁵Royal Liverpool Univ. Hosp., UK

Background: Increased expression of multidrug efflux transporters has been implicated as a potential mechanism for decreased drug availability at intracellular sites that provide sanctuary for HIV. As HIV protease inhibitors are substrates for the efflux transporters P-glycoprotein (P-gp) and MRP1, we investigated whether inter-individual differences in expression of these transporters would impact on the intracellular concentrations of ritonavir (RTV) and saquinavir (SQV). The aim was to determine drug efflux transporter expression and RTV and SQV concentrations in the plasma and peripheral blood mononuclear cells of HIV patients receiving HAART.
Methods: All patients had undetectable plasma viral load (<50 copies/mL) on combination antiretroviral therapy including a protease inhibitor. Patients undergoing treatment with drugs known to be substrates/inhibitors of P-gp or MRP were excluded from the trial. Venous blood samples (25 mL) were collected into lithium heparin tubes at time 0, 2, 4, 8, and 12 hours after supervised ingestion of the regimen which included RTV (n=23) or SQV (n=18). Plasma and intracellular (cell associated) drug concentrations were measured by HPLC/Mass spectrometry. Lymphocyte expression of P-gp and MRP1 was investigated using immunofluorescence and detected by flow cytometry. The ratio of intracellular/plasma drug concentration was calculated to determine the cellular drug accumulation. Statistical analysis of drug accumulation with low and high P-gp and MRP1 expression (stratified about the median) was performed using Mann Whitney U test.
Results: Patients with lower MRP1 expression had a significantly higher accumulation of both RTV and SQV than those with higher MRP1 expression (p=0.035, CI=-1.70-0.06 and p=0.043, CI=-12.79-0.11, respectively). RTV accumulation was significantly greater in patients with lower P-gp expression than in patients with higher expression (p=0.014, CI=-1.56-0.14). There was also a trend towards higher SQV accumulation in patients with lower P-gp expression (p=0.219, CI=-5.02-2.40).
Conclusions: Increased expression of P-gp and MRP1 on lymphocytes is associated with lower intracellular accumulation of SQV and RTV. This suggests that these 2 transporters may play a role in the efflux of RTV and SQV from lymphocytes in HIV-infected patients.

Š2002 9^th Conference on Retroviruses and Opportunistic Infections