Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations

Abstract

Background: Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1.

Methods: The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice.

Results: All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics.

Conclusion: These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI-chemotherapy interactions involving transporters.

Figure 1

Inhibition of OATP1B-type transporters by TKIs. (A) Influence of 16 different TKIs (10 μM; 15-min pre-incubation) on the activity of OATP1B1, expressed in Flp-In T-Rex293 cells, as determined by the intracellular accumulation of [³H]estradiol-17β-D-glucuronide (E2G) (0.1 μM; 5-min incubation). (B) Influence of sorafenib (0.040–40 μM; 15-min pre-incubation) on the activity of OATP1B1, expressed in HEK293 cells, as determined by intracellular accumulation of [³H]docetaxel (0.1 μM; 5-min incubation). The curve was obtained by fitting the Hill equation to the data. (C, D) Influence of sorafenib (10 μM; 15-min pre-incubation) on the intracellular accumulation of [³H]estradiol-17β-D-glucuronide (E2G) (0.1 μM; 5-min incubation) or [³H]docetaxel (0.1 μM; 5-min incubation) in HEK293 cells with or without expression of OATP1B1 (C) or Oatp1b2 (D). All data represent the mean (bar)±s.d. (error bar) of two experiments performed in triplicate (n=6).

Figure 2

Influence of Oatp1b2 deficiency and sorafenib on docetaxel pharmacokinetics. Wild-type, Oatp1b2(−/−), Oatp1a/1b(−/−), or OATP1B1(tg) mice (n=3–11 per group) were given oral vehicle or oral sorafenib (60 mg kg⁻¹) as a single oral dose (denoted ‘single') or twice daily for 4 days (denoted ‘multiple') before i.v. docetaxel (10 mg kg⁻¹). Results represent the mean (symbol)±s.d. (error bar) for the observed peak plasma concentrations (C_max) in panel (A) or the area under the curve extrapolated to infinity (AUC) in panel (B). The corresponding plasma–concentration time profiles and kinetic parameter estimates are provided in Supplementary Figure S1 and Supplementary Table S1, respectively. *P<0.05 compared with the reference group (wild type or OATP1B1(tg)).