Association between ABCC2 polymorphism and lopinavir accumulation in peripheral blood mononuclear cells of HIV-infected patients.
OBJECTIVE
Lopinavir (LPV) is a potent protease inhibitor used in combination with low doses of ritonavir in the treatment of HIV-infected patients. LPV pharmacokinetics is characterized by a large interindividual variability requiring the use of therapeutic drug monitoring in different clinical situations. While the sources of this variability are still unknown, several genetic polymorphisms in biotransformation enzymes or transporter proteins involved in the metabolism and/or the distribution of LPV appear as good candidates. Therefore, the aim of the present study was to investigate the influence of selected genetic polymorphisms on LPV trough plasma concentrations ([LPV](Cmin)), LPV concentrations in peripheral blood mononuclear cells ([LPV](CC)) and the LPV accumulation ratio ([LPV](CC):[LPV](Cmin)).


METHODS
A total of 53 patients receiving Kaletra((R)) (Abbott Laboratories, IL, USA) (LPV+ritonavir) were genotyped for 14 different polymorphisms in biotransformation enzymes and transporter proteins. [LPV](Cmin), [LPV](CC) and [LPV](CC):[LPV](Cmin) were compared according to the patient's genotypes.


CONCLUSIONS
The 4544G>A (rs8187710)polymorphism in ABCC2 was associated with a higher accumulation of LPV in peripheral blood mononuclear cells of HIV-treated patients. As already observed in previous studies, ABCB1 or CYP3A5 polymorphisms had no impact on [LPV](Cmin) and we did not detect any influence of these polymorphisms on [LPV](CC) and its accumulation in mononuclear cells. In conclusion, this pilot study suggests, for the first time, that the 4544G>A polymorphism in ABCC2 could explain a significant part of the interindividual variability in LPV pharmacokinetics. Further investigations are needed to confirm this association and to explore its real pharmacodynamic impact.
Louvain Center for Toxicology and Applied Pharmacology (LTAP), Université Catholique de Louvain, 53.02 Avenue E. Mounier, 1200 Bruxelles, Belgium. laure.elens@uclouvain.be
Laure
L
Elens
Jean-Cyr
JC
Yombi
Dominique
D
Lison
Pierre
P
Wallemacq
Bernard
B
Vandercam
Vincent
V
Haufroid
D000328:Adult; D000483:Alleles; D044383:Black People / Q000235:genetics / Q000706:statistics & numerical data; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D061466:Lopinavir; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D011744:Pyrimidinones / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
D017320:HIV Protease Inhibitors; D061466:Lopinavir; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011744:Pyrimidinones; C000715087:ABCC2 protein, human