Apical ABC Transporters and Cancer Chemotherapeutic Drug Disposition

Breast Cancer Resistance Protein and P-Glycoprotein Influence In Vivo Disposition of 11C-Erlotinib

“…It has now been documented for many dual ABCB1/ABCG2 substrates that these 2 transporters are capable of mutually compensating their function when 1 transporter is knocked out or inhibited (20,21). This phenomenon causes only small increases in brain distribution of ABCB1/ABCG2 substrates when only 1 transporter is absent and disproportionally large increases when both transporters are absent, as was the case for 11 C-erlotinib (Fig.…”

“…Importantly, we could show that radioactivity in the brain after injection of 11 C-erlotinib is mainly in the form of unmetabolized 11 C-erlotinib (Supplemental Table 2) thus making 11 C-erlotinib PET suitable to assess the effect of ABCB1 and ABCG2 on 11 C-erlotinib brain distribution. It is now known that most currently available TKIs (e.g., sorafenib, gefitinib, sunitinib) are dual ABCB1/ABCG2 substrates resulting in low brain distribution (20,21). This is of concern as poor BBB penetration may render these drugs ineffective in the treatment of primary or secondary brain tumors (e.g., gliomas, NSCLC brain metastases) (11,22).…”

“…This is of concern as poor BBB penetration may render these drugs ineffective in the treatment of primary or secondary brain tumors (e.g., gliomas, NSCLC brain metastases) (11,22). Pharmacologic inhibition of ABCB1 and ABCG2 has been suggested as a promising approach to enhance brain distribution of TKIs and thereby increase their efficacy to treat brain tumors (20,22). However, a limitation in realizing this therapeutic concept is the current lack of clinically usable, marketed dual ABCB1/ ABCG2 inhibitors.…”

“…However, a limitation in realizing this therapeutic concept is the current lack of clinically usable, marketed dual ABCB1/ ABCG2 inhibitors. The most potent dual ABCB1/ABCG2 inhibitor known to date is elacridar, which has shown great promise in enhancing brain distribution of dual ABCB1/ABCG2 substrates in preclinical studies (20)(21)(22). We found that 10 mg of elacridar per kilogram given intravenously 20 min before 11 C-erlotinib injection can increase brain distribution of 11 C-erlotinib to an extent similar to that in Abcb1a/b (2/2) Abcg2 (2/2) mice, indicating complete inhibition of Abcb1a/b and Abcg2 at the BBB (Figs.…”

ATP‑binding cassette transporter A1: A promising therapy target for prostate cancer (Review)

“…The ABC-type transporters act as gatekeepers by allowing or limiting the entrance of a wide variety of substrates across cellular membranes (6). A total of 51 ABC transporter genes have been identified and are grouped into seven subfamilies, namely A-G, based on their phylogenetic distance (7). The physiological importance of ABCA subfamily proteins is underscored by their association with various inherited diseases.…”