P-glycoprotein and MRP1 expression and reduced ritonavir and saquinavir accumulation in HIV-infected individuals.
OBJECTIVE
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.


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 (r(2) = 0.195, P = 0.035) and ritonavir (r(2) = 0.220, P = 0.049).


CONCLUSIONS
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.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D019540:Area Under Curve; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019258:Saquinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018709:Statistics, Nonparametric
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019438:Ritonavir; D019258:Saquinavir; C421109:multidrug resistance-associated protein 1