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

Abstract

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 endo- and xenobiotics and have been reported to have functional SNPs. We have assessed the substrate specificites of these transporters for a panel of antiretrovirals and investigated the effects of SNPs within these transporters on the pharmacokinetics of lopinavir. 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. 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. 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.

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

“…34,35 In addition to the OATP1B inhibitory potential of HIV PI, several studies revealed that these drugs also show affinity for OATP1B isoforms as substrates. 19,20 Moreover, the 521T>C gene polymorphism in SLCO1B1 is significantly associated with higher lopinavir plasma concentrations. 20 These findings raise the question whether hepatic OATP isoforms play a pivotal role in the hepatic uptake of HIV PI.…”

“…19,20 Moreover, the 521T>C gene polymorphism in SLCO1B1 is significantly associated with higher lopinavir plasma concentrations. 20 These findings raise the question whether hepatic OATP isoforms play a pivotal role in the hepatic uptake of HIV PI. The aim of this study was to further investigate the exact role of hepatic uptake transport in the overall hepatic Cl of HIV PI.…”

“…20 Furthermore, it has been shown that the single nucleotide polymorphism 521T>C in SLCO1B1 is associated with significantly increased plasma concentrations of lopinavir. 20,21 In contrast, a recent publication showed that the hepatic uptake of nelfinavir, lopinavir and ritonavir is primarily mediated by passive diffusion in sandwichcultured human hepatocytes. 22 Additionally, they suggested an unidentified sinusoidal uptake transporter for amprenavir.…”

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

“…A common SNP in the SLCO1B1 gene, 521T>C, has been associated with higher plasma levels of LPV [64][65][66][67], but the clinical significance is still uncertain and further studies are needed to confirm this association and to assess the impact on LPV pharmacokinetics.…”

Potential role of organic anion transporting polypeptide 1B1 (OATP1B1) in the selective hepatic uptake of hematoporphyrin monomethyl ether isomers

“…Compared with wild-type OATP1B1, c.521T>C was associated with increased systemic exposure to multiple drugs, including oral pravastatin [23,24] , fexofenadine [25] , and lopinavir [26,27] . In addition, the co-administration of OATP1B1 inhibitors may affect the pharmacokinetics of its substrates.…”