PET-CT imaging with [18F]-gefitinib to measure Abcb1a/1b (P-gp) and Abcg2 (Bcrp1) mediated drug–drug interactions at the murine blood–brain barrier

Use of PET Imaging to Evaluate Transporter‐Mediated Drug‐Drug Interactions

“…Inadequate brain delivery of TKIs is probably the most important reason why clinical trials to treat CNS malignancies with TKIs have largely remained without success, even though growth of a considerable percentage of brain tumors may be dependent on activated tyrosine kinases . Several radiolabeled versions of these drugs ([ 11 C]imatinib, [ 11 C]erlotinib, [ 11 C]gefitinib, [ 18 F]gefitinib, [ 11 C]sorafenib, [ 11 C]lapatinib, and [ 18 F]afatinib) have been synthesized, and it was shown that some of these tracers allow studying of the functional interplay of P‐gp and BCRP at the BBB . Transporter‐mediated DDIs resulting in increases in brain distribution of dual P‐gp/BCRP substrates, such as TKIs, would require perpetrator drugs that inhibit both transporters simultaneously at clinically relevant plasma concentrations.…”

“…Such compounds are expected to be very rare. It was shown that pretreatment of wild‐type mice with elacridar, the most potent experimental dual P‐gp/BCRP inhibitor known to date, increased brain exposure of [ 11 C]gefitinib, [ 18 F]gefitinib, or [ 11 C]erlotinib to comparable levels as in Mdr1a/b (‐/‐) Bcrp1 (‐/‐) mice, suggesting that elacridar can completely inhibit P‐gp and BCRP at the mouse BBB . Human PET studies using elacridar as P‐gp/BCRP inhibitor have not so far been reported.…”

“…67 68 and it was shown that some of these tracers allow studying of the functional interplay of P-gp and BCRP at the BBB. 20,69,70 Transporter-mediated DDIs resulting in increases in brain distribution of dual P-gp/BCRP substrates, such as TKIs, would require perpetrator drugs that inhibit both transporters simultaneously at clinically relevant plasma concentrations. Such compounds are expected to be very rare.…”

“…It was shown that pretreatment of wild-type mice with elacridar, the most potent experimental dual P-gp/BCRP inhibitor known to date, increased brain exposure of [ 11 C]gefitinib, [ 18 F]gefitinib, or [ 11 C]erlotinib to comparable levels as in Mdr1a/b (-/-) Bcrp1 (-/-) mice, suggesting that elacridar can completely inhibit P-gp and BCRP at the mouse BBB. 20,69,70 Human PET studies using elacridar as P-gp/BCRP inhibitor have not so far been reported. The radiolabeled P-gp inhibitors [ 11 C]tariquidar and [ 11 C]elacridar have been proposed as generic PET tracers to assess P-gp and BCRP function at the BBB.…”

Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

“…Overall, those results indicated that gefitinib is a substrate of both human and murine efflux transporters, albeit with potential species specific differences in their affinities for the drug [61]. …”