title: Individual differences in rate-limiting reactions during metabolism of irinotecan hydrochloride.
abstract: Irinotecan hydrochloride (CPT-11) is converted to SN-38 by carboxylesterase, SN-38 is conjugated by UDP-glucuronosyl- transferase (UGT) to SN-38G. Individual differences in enzyme activity influence the efficacy of this anticancer agent and the adverse reactions it induces. In this study, individual differences in the metabolism of this drug were determined by calculating its c 1 on version (CPT-11 to SN-38) and conjugation ratios (SN-38 to SN-38G) from blood concentrations of CPT-11, SN-38, and SN-38G at immediately and 60 min after a 90-min intravenous infusion of CPT-11. Changes in conversion and conjugation during long-term infusion of CPT-11 were also investigated. The median conversion and conjugation ratios were 0.0155 and 2.812, respectively (n=48). Based on these values, the patients were classified into four types: low-low type (10.4%), low-high type (31.2%), high-low type (31.2%), and high high type (27.1%). Prolongation of infusion time resulted in an increase in the conversion ratio in the low-high type and an increase in the conjugation ratio in the high-low type. These changes, however, were very slight in the high-high type. Thus, a longer infusion time made it possible to increase the number of doses in the low-high type and minimize adverse reactions in the high-low type.
  
  
  CONCLUSIONS
  In patients found to have a low SN-38 conversion ratio or SN-38G conjugation ratio based on simple assessment of data obtained by 2-point blood sampling, modification of infusion time may allow pharmacokinetic changes that confer a clinical benefit.
authors.affiliation: Department of Pharmacy, National Hospital Organization, Osaka Minami Medical Center, Kawachinagano, Osaka, Japan.
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Morimoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Matsuura
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Shono
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Horiuchi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyabe
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Hachino
authors.forename: Kenji
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Matsuyama
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Fujita
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Tabuse
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007206:Individuality; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin