title: Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia.
abstract: Using broad interrogation of clinically relevant drug absorption, distribution, metabolism, and excretion (ADME) genes on the DMET platform, we identified a genetic variant in SLCO1B1 (rs2291075; c.597C>T), encoding the transporter OATP1B1, associated with event-free (P = 0.006, hazard ratio = 1.74) and overall survival (P = 0.012, hazard ratio = 1.85) in children with de novo acute myeloid leukemia (AML). Lack of SLCO1B1 expression in leukemic blasts suggested the association might be due to an inherited rather than a somatic effect. rs2291075 was in strong linkage with known functional variants rs2306283 (c.388A>G) and rs4149056 (c.521T>C). Functional studies in vitro determined that four AML-directed chemotherapeutics (cytarabine, daunorubicin, etoposide, and mitoxantrone) are substrates for OATP1B1 and the mouse ortholog Oatp1b2. In vivo pharmacokinetic studies using Oatp1b2-deficient mice further confirmed our results. Collectively, these findings demonstrate an important role for OATP1B1 in the systemic pharmacokinetics of multiple drugs used in the treatment of AML and suggest that inherited variability in host transporter function influences the effectiveness of therapy.
authors.affiliation: College of Pharmacy Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus, Ohio, USA.|Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Drenberg
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Paugh
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Pounds
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.affiliation: Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Orwick
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: College of Pharmacy Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus, Ohio, USA.|Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.affiliation: College of Pharmacy Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus, Ohio, USA.|Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Ribeiro
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Rubnitz
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: College of Pharmacy Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus, Ohio, USA.|Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
authors.affiliation: College of Pharmacy Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus, Ohio, USA.|Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000627:therapeutic use; D002648:Child; D015331:Cohort Studies; D003561:Cytarabine / Q000493:pharmacokinetics; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; D003561:Cytarabine; D004247:DNA