HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms.
OBJECTIVE
OATP1B1 and OATP1B3 are major hepatic drug transporters whilst OATP1A2 is mainly located in the brain but is also located in liver and several other organs. These transporters affect the distribution and clearance of many endobiotics and xenobiotics and have been reported to have functional single nucleotide polymorphisms (SNPs). We have assessed the substrate specificities of these transporters for a panel of antiretrovirals and investigated the effects of SNPs within these transporters on the pharmacokinetics of lopinavir.


METHODS
SLCO1A2, SLCO1B1 and SLCO1B3 were cloned, verified and used to generate cRNA for use in the Xenopuslaevis oocyte transport system. Using the oocyte system, antiretrovirals were tested for their substrate specificities. Plasma samples (n=349) from the Liverpool therapeutic drug monitoring registry were genotyped for SNPs in SLCO1A2, SLCO1B1 and SLCO1B3 and associations between SNPs and lopinavir plasma concentrations were analysed.


RESULTS
Antiretroviral protease inhibitors, but not non-nucleoside reverse transcriptase inhibitors, are substrates for OATP1A2, OATP1B1 and OATP1B3. Furthermore, ritonavir was not an inhibitor of OATP1B1. The 521T>C polymorphism in SLCO1B1 was significantly associated with higher lopinavir plasma concentrations. No associations were observed with functional variants of SLCO1A2 and SLCO1B3.


CONCLUSIONS
These data add to our understanding of the factors that contribute to variability in plasma concentrations of protease inhibitors. Further studies are now required to confirm the association of SLCO1B1 521T>C with lopinavir plasma concentrations and to assess the influence of other polymorphisms in the SLCO family.
Hartkoorn
Ruben C
RC
Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK.
Kwan
Wai San
WS
Shallcross
Victoria
V
Chaikan
Ammara
A
Liptrott
Neill
N
Egan
Deirdre
D
Sora
Enrique Salcedo
ES
James
Chloë E
CE
Gibbons
Sara
S
Bray
Pat G
PG
Back
David J
DJ
Khoo
Saye H
SH
Owen
Andrew
A
D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003001:Cloning, Molecular; D016903:Drug Monitoring; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000187:drug effects; D011744:Pyrimidinones / Q000097:blood* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012042:Registries; D019438:Ritonavir / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013379:Substrate Specificity / Q000187:drug effects; D014981:Xenopus; D055815:Young Adult
D017320:HIV Protease Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011744:Pyrimidinones; D012333:RNA, Messenger; C512988:SLCO1A2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D061466:Lopinavir; D004970:Estrone; D019438:Ritonavir; C017296:estrone sulfate