title: Pharmacogenetic study of deferasirox, an iron chelating agent.
abstract: Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing -1774 del and/or -24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79-28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7-43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34-150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Hyoung Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Ji-Yeob
authors.initials: JY
authors.lastname: Choi
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Kim
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Jang
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Yeo
authors.forename: Sang Seop
authors.initials: SS
authors.lastname: Lee
authors.forename: Hyery
authors.initials: H
authors.lastname: Kim
authors.forename: June Dong
authors.initials: JD
authors.lastname: Park
authors.forename: Kyung Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Hyo Seop
authors.initials: HS
authors.lastname: Ahn
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D001565:Benzoates / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D000077588:Deferasirox; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007223:Infant; D007502:Iron Chelating Agents / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D014230:Triazoles / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001565:Benzoates; D003404:Creatinine; D000077588:Deferasirox; D014453:Glucuronosyltransferase; D007502:Iron Chelating Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D014230:Triazoles; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human