title: Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.
abstract: OBJECTIVE
  ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751.
  
  
  METHODS
  UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes.
  
  
  RESULTS
  UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009).
  
  
  CONCLUSIONS
  These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.
authors.affiliation: Eshelman School of Pharmacy, Lineberger Comprehensive Cancer Center, Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina 27599, USA. innocent@unc.edu
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramírez
authors.forename: Jennifer
authors.initials: J
authors.lastname: Obel
authors.forename: Julia
authors.initials: J
authors.lastname: Xiong
authors.forename: Snezana
authors.initials: S
authors.lastname: Mirkov
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chiu
authors.forename: David A
authors.initials: DA
authors.lastname: Katz
authors.forename: Robert A
authors.initials: RA
authors.lastname: Carr
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Araba
authors.initials: A
authors.lastname: Adjei
authors.forename: Ann M
authors.initials: AM
authors.lastname: Moyer
authors.forename: Pei Xian
authors.initials: PX
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Krivoshik
authors.forename: Diane
authors.initials: D
authors.lastname: Medina
authors.forename: Gary B
authors.initials: GB
authors.lastname: Gordon
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sahelijo
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.forename: Anahita
authors.initials: A
authors.lastname: Bhathena
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D015239:Arylsulfotransferase / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000493:pharmacokinetics*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000493:pharmacokinetics*
chemical_list: C490492:ABT751; D000970:Antineoplastic Agents; D013449:Sulfonamides; D050257:Tubulin Modulators; C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human