title: Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI.
abstract: BACKGROUND
  Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods.
  
  
  METHODS
  Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5.
  
  
  RESULTS
  SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype.
  
  
  CONCLUSIONS
  Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00808184.
authors.affiliation: Department of Medicine, National University Health System, Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Lawrence Soon-U
authors.initials: LS
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Kok-Yong
authors.initials: KY
authors.lastname: Seng
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.|Cancer Science Institute, National University of Singapore, Singapore, Singapore.
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Kim-Hor
authors.initials: KH
authors.lastname: Hee
authors.affiliation: Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Soh
authors.affiliation: Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wong
authors.affiliation: Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
authors.forename: Pei F
authors.initials: PF
authors.lastname: Cheong
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Nur S
authors.initials: NS
authors.lastname: Sapari
authors.affiliation: Department of Medicine, National University Health System, Singapore, Singapore.|Department of Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Ross
authors.initials: R
authors.lastname: Soo
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore, Singapore.
authors.forename: Lu
authors.initials: L
authors.lastname: Fan
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore, Singapore.|Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.|Cancer Science Institute, National University of Singapore, Singapore, Singapore.|Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
authors.forename: Boon C
authors.initials: BC
authors.lastname: Goh
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D000068898:Raltegravir Potassium / Q000493:pharmacokinetics*; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000068898:Raltegravir Potassium; D000099148:UGT1A1 Enzyme