The impact of SLCO1B1 polymorphisms on the plasma concentration of lopinavir and ritonavir in HIV-infected men.
BACKGROUND
* There is large interindividual variability in the pharmacokinetics of protease inhibitors (PIs) among human immunodeficiency virus (HIV)-infected individuals under highly active antiretroviral therapy. * Protease inhibitor have been recently reported to be substrates of the SLCO1B1/OATP1 drug transporter. * A single nucleotide polymorphism (SNP) in the SLCO1B1 gene (521T-->C) was associated with plasma levels of lopinavir in HIV-infected individuals.


CONCLUSIONS
* Data on the impact of three SLCO1B1 SNPs (521T-->C, 388A-->G, 463C-->A) on the trough plasma concentration of lopinavir and ritonavir in a cohort of 99 adult HIV-infected Brazilian men under stable highly active antiretroviral therapy. * Evidence that carriers of the 521C allele display significantly higher lopinavir, but not ritonavir plasma concentrations relative to the wild-type TT genotype. * No effect of either 388A-->G or 463C-->A SNPs on lopinavir or ritonavir plasma concentrations. * Further studies are required to confirm the clinical significance of the association between the SLCO1B1521T-->C polymorphism and lopinavir pharmacokinetics.


OBJECTIVE
To investigate possible associations between three SLCO1B1 single nucleotide polymorphisms (388A-->G, 463C-->A, 521T-->C) and lopinavir/ritonavir plasma concentrations.


METHODS
The study included 99 human immunodeficiency virus-infected men on stable highly active antiretroviral therapy containing lopinavir/ritonavir. Trough concentrations of lopinavir and ritonavir in plasma were quantified using liquid chromatography-tandem mass spectrometry. Genotyping of SLCO1B1388A-->G, 463C-->A and 521T-->C polymorphisms was performed by allelic discrimination using real-time polymerase chain reaction.


RESULTS
The trough concentration of lopinavir in plasma is significantly associated with SLCO1B1521T-->C genotypes (P= 0.03). There is a significant trend for increasing concentrations of lopinavir from TT to TC to CC genotypes (P= 0.02). Carriers of the 521C allele display significantly higher lopinavir plasma concentrations relative to the wild-type TT genotype (P= 0.03).


CONCLUSIONS
Reduced uptake of lopinavir by hepatocytes in carriers of the 521C allele may account for these results, but further studies to confirm the clinical importance of SLCO1B1 polymorphisms in lopinavir pharmacokinetics are warranted.
Kohlrausch
Fabiana B
FB
Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
de Cássia Estrela
Rita
R
Barroso
Paulo F
PF
Suarez-Kurtz
Guilherme
G
D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D002853:Chromatography, Liquid; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D061466:Lopinavir; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011744:Pyrimidinones / Q000097:blood* / Q000627:therapeutic use; D019438:Ritonavir / Q000097:blood* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry
D019380:Anti-HIV Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011744:Pyrimidinones; C503999:SLCO1B1 protein, human; D061466:Lopinavir; D019438:Ritonavir