Abstract 3785: Human pharmacokinetics (PK) of selected tyrosine kinase inhibitors (TKI) in relation to transport characteristics in a polarized gut epithelium model system

TKI represent the largest group of novel anticancer drugs. Loosely based on a core pyrimidine structure TKI selectively target the ATP activity of a TK. Their poor solubility represents a challenge in administration. TKI are administered orally but available PK indicates that in most cases bioavailability is relatively low (∼60% or lower). Despite a molecular weight in a similar range, doses vary significantly: Sunitinib (Sun) - 50 mg/d, Dasatinib (Das) - 150 mg/d, Erlotinib (Erl) - 150 mg/d, Gefitinib (Gef) - 250 mg/d and Sorafenib (Sor) - 400 mg BID. Steady state plasma levels vary from 0.13 (Sun), 0.21 (Das), 0.29 (Gef), 2.54 (Erl) to 12.1 µM (Sor). In combination Erl increased systemic plasma levels of Sor. Variations in intestinal absorption may seriously affect plasma concentrations, tumour exposure and anti tumour effect. To investigate the mechanisms behind these differences a well established model for intestinal transport was used: the human colon cell line, CaCo2, when grown in special coated Transwell plates forms a confluent differentiated polarised monolayer resembling gut epithelium. This model was used to determine the permeability of Gef, Erl, Sun, Sor, Das and combined Erl/Sor. Absorption from the gut given as the transfer rates from Apical to Basolateral (A/B) sides using 20 µM TKI at the apical side was determined over a 3 hour period. Transfer was linear in this period. Transfer rates varied from 43 for Sun, 209 for Das, 180 for Gef, 223 for Sor, to 479 pmol/hr for Erl. At 10 µM Erl increased transfer rate of Sor from 145 to 185.7 pmol/hr in line with observed plasma levels. In order to determine the role of ABC pumps, we depleted ATP with azide, which partially reduced transfer of Gef, Sun and Sor, but did not affect Erl. Ko143, a specific ABCG2 inhibitor decreased transfer of Gef and Sor but unexpectedly increased Sun. Remarkably, permeability transfer rates from the basolateral (blood) side to gut (B/A) were much higher (252 for Gef, 621 for Sor, 685 for Sun, 1623 for Erl and 4630 pmol/hr for Das) than A/B transfer. In order to explain this difference we determined cellular accumulation in the monolayer cells at the end of the experiments. For the A/B experiments this was undetectable for Erl, 0.79 for Gef, 1.65 for Sor, 11.9 for Sun and 1.1 for Das (pmol/µg protein). For the B/A experiments a proportional decrease in accumulation relative to the observed increased transfer rate was seen with Gef as the exception, with values from undetectable for Erl, 2.1 for Gef, 0.15 for Sor, 4.72 for Sun and 0.26 pmol/µg protein for Das. In conclusion, absorption of TKI from the apical side (gut epithelium) is relatively poor, while there was a relatively high negative flow (B/A); this is in line with the low bioavailability of most TKI. Some ABC transporters play a role in the absorption, in line with their substrate specificity. This may also affect retention of TKI in tumour cells Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3785. doi:1538-7445.AM2012-3785