title: [Influence of genetic polymorphisms in UGT1A1, UGT1A7 and UGT1A9 on the pharmacokynetics of irinotecan, SN-38 and SN-38G].
abstract: OBJECTIVE
  To evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G.
  
  
  METHODS
  Plasma concentrations of irinotecan, SN-38 and SN- 38G from 72 patients were pooled to develop a population pharmacokinetic model using NONMEM VII. M3 method was used to account for plasma concentrations below the limit quantification. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. The model was internally validated using normalized visual predictive check (NVPC) and normalized predictive distribution errors (NPDE).
  
  
  RESULTS
  The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. The presence of UGT1A1*28, UGT1A7*3, UGT1A9*22 genotypes decreases SN-38 clearance between 20 and 36%. Internal validation confirms the population pharmacokinetic model describe the time course of irinotecan, SN-38 and SN-38G plasma concentration and their associated variability in cancer patients.
  
  
  CONCLUSIONS
  The inclusion of pharmacokinetic-pharmacogenomic information can add value to the individualized dose adjustment of irinotecan, because it will let quantitatively handle dose reductions in patients with iatrogenic toxicity due to UGT1A1 genetic polymorphisms.
authors.forename: B
authors.initials: B
authors.lastname: Valenzuela Jiménez
authors.forename: M
authors.initials: M
authors.lastname: González Sales
authors.forename: V
authors.initials: V
authors.lastname: Escudero Ortiz
authors.forename: E
authors.initials: E
authors.lastname: Martínez Navarro
authors.forename: C
authors.initials: C
authors.lastname: Pérez Ruixo
authors.forename: J
authors.initials: J
authors.lastname: Rebollo Liceaga
authors.forename: R
authors.initials: R
authors.lastname: González Manzano
authors.forename: J J
authors.initials: JJ
authors.lastname: Pérez Ruixo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005965:Glucuronates / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D011110:Polymorphism, Genetic; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D005965:Glucuronates; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; C000715591:UGT1A9 protein, human; C524630:UGT1A7 protein, human