{"doi":"10.3390/molecules27206815","title":"Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B","abstract":"Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole. However, the precise mechanism by which itraconazole and other CYP3A-modulating drugs affect the absorption and disposition of gilteritinib remains unclear. In the present investigation, we demonstrate that pretreatment with itraconazole is associated with a significant increase in the systemic exposure to gilteritinib in mice, recapitulating the observed clinical drug-drug interaction. However, the plasma levels of gilteritinib were only modestly increased in CYP3A-deficient mice and not further influenced by itraconazole. Ensuing in vitro and in vivo studies revealed that gilteritinib is a transported substrate of OATP1B-type transporters, that gilteritinib exposure is increased in mice with OATP1B2 deficiency, and that the ability of itraconazole to inhibit OATP1B-type transport in vivo is contingent on its metabolism by CYP3A isoforms. These findings provide new insight into the pharmacokinetic properties of gilteritinib and into the molecular mechanisms underlying drug-drug interactions with itraconazole.","journal":"Molecules","year":2022,"id":274505,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9471,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":570273,"name":"Yan Jin","orcid":"0000-0002-4124-3362","position":1,"is_corresponding":false},{"id":355832,"name":"Zahra Talebi","orcid":"0000-0001-9166-5160","position":2,"is_corresponding":false},{"id":255307,"name":"Shuiying Hu","orcid":"0000-0002-9806-7734","position":3,"is_corresponding":false},{"id":255308,"name":"Alex Sparreboom","orcid":"0000-0003-2660-6644","position":4,"is_corresponding":false},{"id":342107,"name":"Sharyn D. Baker","orcid":"0000-0003-3062-3252","position":5,"is_corresponding":false},{"id":310489,"name":"Eric D. Eisenmann","orcid":"0000-0003-1176-675X","position":6,"is_corresponding":false},{"id":355831,"name":"Dominique A. Garrison","orcid":"0000-0002-7250-9346","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T00:28:12.324621Z","pmid":"36296409","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}