Abstract
Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important hepatic transporters that mediate the uptake of many clinically important drugs, including statins from the blood into the liver. Reduced transport function of OATP1B1 and OATP1B3 can lead to clinically relevant drug-drug interactions (DDIs). Considering the importance of OATP1B1 and OATP1B3 in hepatic drug disposition, substantial efforts have been given on evaluating OATP1B1/1B3-mediated DDIs in order to avoid unwanted adverse effects of drugs that are OATP substrates due to their altered pharmacokinetics. Growing evidences suggest that the transport function of OATP1B1 and OATP1B3 can be regulated at various levels such as genetic variation, transcriptional and post-translational regulation. The present review summarizes the up to date information on the regulation of OATP1B1 and OATP1B3 transport function at different levels with a focus on potential impact on OATP-mediated DDIs.
Highlights
Membrane transporter proteins play important roles in facilitating the translocation of endogenous compounds and xenobiotics across biological membranes
Another report in 2014 found that mRNA expression of OATP1B1 and 1B3 in the liver was significantly reduced at the younger ages when compared to adult expression, where OATP1B1 and 1B3 mRNA expression levels were reduced by 500- and 600-fold in neonates and 90- and 100-fold in infants when compared to adults, respectively [112]
In OATP1B1- and OATP1B3-expressing stable cell lines and human sandwich-cultured hepatocytes (SCH), treatment with lysosome inhibitor chloroquine markedly increased protein levels of OATP1B1 and 1B3, suggesting that the lysosome plays an important role in degradation of OATP1B1 and OATP1B3 [138,161]
Summary
Membrane transporter proteins play important roles in facilitating the translocation of endogenous compounds and xenobiotics across biological membranes. Nonsynonymous SNPs of OATP1B3 (T334G, G699A) that are in complete linkage disequilibrium [50] have been reported In vitro, this OATP1B3 variant protein (i.e., 334G–699A haplotype) has reduced transport activity toward mycophenolic acid glucuronide (MPAG) compared with the reference OATP1B3 protein. Drugs that are OATP1B1/1B3 inhibitors (e.g., gemfibrozil, cyclosporine A, rifampicin and ritonavir) may cause clinically significant adverse effects, such as myopathy, when co-administered with lipid-lowering statins, which are substrates of OATPs [54,55,56,57]. Such drug-drug interactions (DDIs) may lead to life-threatening rhabdomyolysis in severe cases [58]. 1.4 [94] 15 [67] 2.0 [96] 1.4 [98] 1.6 [86] 2 [99], 4.6–5.2 [79], 5 [100] 2.8 [72] 1.3 [102]
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