Intracellular concentration of protease inhibitors in HIV-1-infected patients: correlation with MDR-1 gene expression and low dose of ritonavir.
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.


METHODS
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 log(10)) 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).


CONCLUSIONS
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.
Chaillou
S
S
Service des Maladies Infectieuses, Hôpital Archet 1, Nice, France. chaillou.s@chu-nice.fr
Durant
J
J
Garraffo
R
R
Georgenthum
E
E
Roptin
C
C
Clevenbergh
P
P
Dunais
B
B
Mondain
V
V
Roger
P M
PM
Dellamonica
P
P
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D002219:Carbamates; D017931:DNA Primers; D004334:Drug Administration Schedule; D005260:Female; D005663:Furans; D005786:Gene Expression Regulation; D019450:Genes, MDR / Q000235:genetics*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D019888:Nelfinavir / Q000008:administration & dosage; D010865:Pilot Projects; D012333:RNA, Messenger / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019258:Saquinavir / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D019562:Viral Load
D002219:Carbamates; D017931:DNA Primers; D005663:Furans; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir