TY - JOUR
T1 - Epithelial transfer of the tyrosine kinase inhibitors erlotinib, gefitinib, afatinib, crizotinib, sorafenib, sunitinib, and dasatinib: Implications for clinical resistance
AU - Honeywell, Richard J.
AU - Kathmann, Ietje
AU - Giovannetti, Elisa
AU - Tibaldi, Carmelo
AU - Smit, Egbert F.
AU - Rovithi, Maria N.
AU - Verheul, Henk M. W.
AU - Peters, Godefridus J.
N1 - Funding Information: Funding: No external funding was obtained for this study, which was financed out of departmental funds. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Background: tyrosine kinase inhibitors (TKIs) inhibit phosphorylation of signaling proteins. TKIs often show large variations in the clinic due to poor pharmacology, possibly leading to resistance. We compared gut absorption of inhibitors of epidermal growth factor receptor (erlotinib, gefitinib, and afatinib), ALK-cMET (crizotinib), PDGFR/BCR-Abl (dasatinib), and multikinase inhibitors (sunitinib and sorafenib). In clinical samples, we measured the disposition of each compound within various blood compartments. Methods: we used an optimized CaCo2 gut epithelial model to characterize 20 µM TKI absorption. The apical/basolateral transfer is considered to represent the gut/blood transfer. Drugs were measured using LC-MS/MS. Results: sorafenib and sunitinib showed the highest apical/basolateral transfer (Papp 14.1 and 7.7 × 10−6 cm/s, respectively), followed by dasatinib (3.4), afatinib (1.5), gefitinib (0.38), erlotinib (0.13), and crizotinib (n.d.). However, the net absorptions for dasatinib, afatinib, crizotinib, and erlotinib were highly negative (efflux ratios >5) or neutral/negative, sorafenib (0.86), gefitinib (1.0), and sunitinib (1.6). A high negative absorption may result in resistance because of a poor exposure of tissues to the drug. Accumulation of the TKIs at the end of the transfer period (A->B) was not detectable for erlotinib, very low for afatinib 0.45 pmol/μg protein), followed by gefitinib (0.79), dasatinib (1.1), sorafenib (1.65), and crizotinib (2.11), being highest for sunitinib (11.9). A similar pattern was found for accumulation of these drugs in other colon cell lines, WiDr and HT29. In clinical samples, drugs accumulated consistently in red blood cells; blood to plasma ratios were all > 3 (sorafenib) or over 30 for erlotinib. Conclusions: TKIs are consistently poorly absorbed, but accumulation in red blood cells seems to compensate for this.
AB - Background: tyrosine kinase inhibitors (TKIs) inhibit phosphorylation of signaling proteins. TKIs often show large variations in the clinic due to poor pharmacology, possibly leading to resistance. We compared gut absorption of inhibitors of epidermal growth factor receptor (erlotinib, gefitinib, and afatinib), ALK-cMET (crizotinib), PDGFR/BCR-Abl (dasatinib), and multikinase inhibitors (sunitinib and sorafenib). In clinical samples, we measured the disposition of each compound within various blood compartments. Methods: we used an optimized CaCo2 gut epithelial model to characterize 20 µM TKI absorption. The apical/basolateral transfer is considered to represent the gut/blood transfer. Drugs were measured using LC-MS/MS. Results: sorafenib and sunitinib showed the highest apical/basolateral transfer (Papp 14.1 and 7.7 × 10−6 cm/s, respectively), followed by dasatinib (3.4), afatinib (1.5), gefitinib (0.38), erlotinib (0.13), and crizotinib (n.d.). However, the net absorptions for dasatinib, afatinib, crizotinib, and erlotinib were highly negative (efflux ratios >5) or neutral/negative, sorafenib (0.86), gefitinib (1.0), and sunitinib (1.6). A high negative absorption may result in resistance because of a poor exposure of tissues to the drug. Accumulation of the TKIs at the end of the transfer period (A->B) was not detectable for erlotinib, very low for afatinib 0.45 pmol/μg protein), followed by gefitinib (0.79), dasatinib (1.1), sorafenib (1.65), and crizotinib (2.11), being highest for sunitinib (11.9). A similar pattern was found for accumulation of these drugs in other colon cell lines, WiDr and HT29. In clinical samples, drugs accumulated consistently in red blood cells; blood to plasma ratios were all > 3 (sorafenib) or over 30 for erlotinib. Conclusions: TKIs are consistently poorly absorbed, but accumulation in red blood cells seems to compensate for this.
KW - CaCo2 model system
KW - Efflux ratio
KW - Gut-epithelial transfer
KW - Red blood cell accumulation
KW - Tyrosine kinase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85096639935&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers12113322
DO - https://doi.org/10.3390/cancers12113322
M3 - Article
C2 - 33182766
SN - 2072-6694
VL - 12
SP - 1
EP - 18
JO - Cancers
JF - Cancers
IS - 11
M1 - 3322
ER -