Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia.
OBJECTIVE
Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration.


METHODS
Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype.


RESULTS
Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 μmol/L; K(i) = 11.7 μmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure.


CONCLUSIONS
This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.
Clinical Pharmacology Program, Pharmacology and Experimental Therapeutics Section, Molecular Pharmacology Section, Biostatistics and Data Management Branch, Medical Oncology Branch, and HIV/AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Cody J
CJ
Peer
Tristan M
TM
Sissung
Aerang
A
Kim
Lokesh
L
Jain
Sukyung
S
Woo
Erin R
ER
Gardner
C Tyler
CT
Kirkland
Sarah M
SM
Troutman
Bevin C
BC
English
Emily D
ED
Richardson
Joel
J
Federspiel
David
D
Venzon
William
W
Dahut
Elise
E
Kohn
Shivaani
S
Kummar
Robert
R
Yarchoan
Giuseppe
G
Giaccone
Brigitte
B
Widemann
William D
WD
Figg
D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D001663:Bilirubin / Q000378:metabolism; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010597:Pharmacogenetics; D010671:Phenylurea Compounds; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D000077157:Sorafenib; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D001663:Bilirubin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009536:Niacinamide; D010671:Phenylurea Compounds; D011725:Pyridines; D000077157:Sorafenib; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human; C000715591:UGT1A9 protein, human