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HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms

Hartkoorn, Ruben C.a; Kwan, Wai Sana; Shallcross, Victoriaa; Chaikan, Ammaraa; Liptrott, Neillc; Egan, Deirdrec; Sora, Enrique Salcedob; James, Chloë E.a; Gibbons, Saraa; Bray, Pat G.b; Back, David J.a; Khoo, Saye H.a; Owen, Andrewa

doi: 10.1097/FPC.0b013e328335b02d
Original Articles

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 Xenopus laevis 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.

Result 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.

Conclusion 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.

aDepartment of Pharmacology and Therapeutics, University of Liverpool

bMolecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Liverpool

cNIHR Biomedical Research Centre, Royal Liverpool and Broadgreen University Hospitals Trust, UK

Correspondence to Dr Andrew Owen, PhD, Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK

Tel: +44 151 794 5919; fax +44 151 794 5656; e-mail:

Ruben C. Hartkoorn and Wai San Kwan are co-authors of the article

Received 16 June 2009 Accepted 24 November 2009

© 2010 Lippincott Williams & Wilkins, Inc.