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. 2014;29(3):179-90.
doi: 10.1515/dmdi-2013-0062.

Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors

Varun Khurana, Mukul Minocha, Dhananjay Pal, Ashim K Mitra

Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors

Varun Khurana et al. Drug Metabol Drug Interact. 2014.

Abstract

Background: The metabolism of tyrosine kinase inhibitors (TKIs) is mainly mediated via hepatic route, but the mechanism responsible for their hepatocellular accumulation is still unknown. This study was designed to understand the contribution of organic anion transporting polypeptides (OATPs) in the hepatic uptake of selected TKIs - pazopanib, canertinib, erlotinib, vandetanib and nilotinib.

Methods: Michaelis-Menten (MM) kinetic parameters for TKIs were determined by concentration-dependent cellular accumulation of selected TKIs using Chinese hamster ovary cells - wild type as well as transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins.

Results: The MM constant (Km) values of OATP-1B1 for nilotinib and vandetanib are 10.14±1.91 and 2.72±0.25 μM, respectively, and Vmax values of OATP-1B1 for nilotinib and vandetanib were 6.95±0.47 and 75.95±1.99 nmol/mg protein per minute, respectively. Likewise, Km values of OATP-1B3 for canertinib, nilotinib and vandetanib were 12.18±3.32, 7.84±1.43 and 4.37±0.79 μM, respectively, and Vmax values of OATP-1B3 for canertinib, nilotinib and vandetanib were 15.34±1.59, 6.75±0.42 and 194.64±10.58 nmol/mg protein per minute, respectively. Canertinib did not exhibit any substrate specificity toward OATP-1B1. Also, erlotinib and pazopanib did not exhibit any substrate specificity toward OATP-1B1 and -1B3.

Conclusions: Because selected TKIs are the substrates of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated drug-drug interactions (DDIs). Any alteration in the function of these hepatic OATPs might account for the pharmacokinetic variability of TKIs.

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Conflict of interest statement

Conflict of interest statement: Authors' conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research support played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Figures

Figure 1
Figure 1
Cellular accumulation of TKIs at two concentrations (0.25 and 0.5 μM) by OATP-1B1 transporter. TKIs were incubated with WT and CHO-OATP-1B1 transfected CHO cells for 10 min. Intracellular drug concentration was quantified using LC/MS-MS. Data represent the mean±SD, n=4 (*p
Figure 2
Figure 2
Cellular accumulation of TKIs at two concentrations (0.25 and 0.5 μM) by OATP-1B3 transporter. TKIs were incubated with WT and OATP-1B3 transfected CHO cells for 10 min. Intracellular drug concentration was quantified using LC/MS-MS. Data represent the mean±SD, n=4 (*p
Figure 3
Figure 3
Concentration-dependent uptake of TKIs in OATP-1B1 transfected CHO cells. (A) Concentration-dependent uptake of nilotinib in OATP-1B1 transfected CHO cells. OATP-1B1 mediated nilotinib transport determined as the difference in uptake in OATP-1B1 and WT CHO cells at each substrate concentration. (B) Concentration-dependent uptake of vandetanib in OATP-1B1 transfected CHO cells. OATP-1B1 mediated vandetanib transport determined as the difference in uptake in OATP-1B1 and WT CHO cells at each substrate concentration. (C) Concentration-dependent uptake of canertinib in WT and OATP-1B1 transfected CHO cells. (D) Concentration-dependent uptake of pazopanib in WT and OATP-1B1 transfected CHO cells. (E) Concentration-dependent uptake of erlotinib in WT and OATP-1B1 transfected CHO cells. Each data point is expressed as mean±SD, n=4.
Figure 4
Figure 4
Concentration-dependent uptake of TKIs in OATP-1B3 transfected CHO cells. (A) Concentration-dependent uptake of canertinib in OATP-1B3 transfected CHO cells. OATP-1B3 mediated canertinib transport determined as the difference in uptake in OATP-1B3 and WT CHO cells at each substrate concentration. (B) Concentration-dependent uptake of nilotinib in OATP-1B3 transfected CHO cells. OATP-1B3 mediated nilotinib transport determined as the difference in uptake in OATP-1B3 and WT CHO cells at each substrate concentration. (C) Concentration-dependent uptake of vandetanib in OATP-1B3 transfected CHO cells. OATP-1B3 mediated vandetanib transport determined as the difference in uptake in OATP-1B3 and WTCHO cells at each substrate concentration. (D) Concentration-dependent uptake of pazopanib in WT and OATP-1B3 transfected CHO cells. (E) Concentration-dependent uptake of erlotinib in WT and OATP-1B3 transfected CHO cells. Each data point is expressed as mean±SD, n=4.
Figure 5
Figure 5
Cytotoxicity in the presence of TKIs at the highest studied concentration (50 μM) on CHO-WT and OATP-1B1- and -1B3-transfected cells. Data represent the mean±SD, n=4.
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References

    1. Shimizu M, Fuse K, Okudaira K, Nishigaki R, Maeda K, Kusuhara H, et al. Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2005;33:1477–81. - PubMed
    1. Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. 2004;447:653–65. - PubMed
    1. Barton HA, Lai Y, Goosen TC, Jones HM, El-Kattan AF, Gosset JR, et al. Model-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond. Expert Opin Drug Metab Toxicol. 2013;9:459–72. - PubMed
    1. Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos. 2013;34:45–78. - PubMed
    1. Zimmerman EI, Hu S, Roberts JL, Gibson AA, Orwick SJ, Li L, et al. Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013;19:1458–66. - PMC - PubMed

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