Influence of phenytoin on the disposition of irinotecan: A case report

Daryl J. Murry, Irene Cherrick, Veronia Salama, Stacey Berg, Mark Bernstein, Nancy Kuttesch, Susan M. Blaney

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Irinotecan (CPT-11), a water-soluble topoisomerase I inhibitor, is metabolized by carboxylesterase enzymes to form an active metabolite, SN-38. Recent studies have shown that irinotecan also undergoes oxidative metabolism by the P450 isozyme CYP3A4, leading to the formation of a minor inactive metabolite, 7-ethyl-10-[4-N-[(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). The elucidation of this metabolic pathway suggests the potential for drug interactions when irinotecan is administered with other inducers or substrates of CYP3A4. In this report, the authors summarize the pharmacokinetic profile of irinotecan and its major metabolites with and without concomitant phenytoin administration in an individual patient. These studies revealed that concomitant phenytoin administration resulted in a marked decrease in the systemic exposure to irinotecan and SN-38 and an increase in the exposure to APC. The area under the curve of irinotecan and SN-38 decreased by 63% and 60%, respectively; the area under the curve of APC increased by approximately 16%. Further detailed pharmacokinetic studies of irinotecan in patients receiving concomitant therapy with enzyme-inducing anticonvulsants are required so that rational dosing recommendations can be provided for this patient population.

Original languageEnglish (US)
Pages (from-to)130-133
Number of pages4
JournalAmerican Journal of Pediatric Hematology/Oncology
Volume24
Issue number2
DOIs
StatePublished - Jan 1 2002

Fingerprint

irinotecan
Phenytoin
Cytochrome P-450 CYP3A
Area Under Curve
Pharmacokinetics
Topoisomerase I Inhibitors
Enzyme Therapy

Keywords

  • CYP3A4
  • Irinotecan
  • Pharmacokinetics
  • Phenytoin
  • SN-38

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Influence of phenytoin on the disposition of irinotecan : A case report. / Murry, Daryl J.; Cherrick, Irene; Salama, Veronia; Berg, Stacey; Bernstein, Mark; Kuttesch, Nancy; Blaney, Susan M.

In: American Journal of Pediatric Hematology/Oncology, Vol. 24, No. 2, 01.01.2002, p. 130-133.

Research output: Contribution to journalArticle

Murry, Daryl J. ; Cherrick, Irene ; Salama, Veronia ; Berg, Stacey ; Bernstein, Mark ; Kuttesch, Nancy ; Blaney, Susan M. / Influence of phenytoin on the disposition of irinotecan : A case report. In: American Journal of Pediatric Hematology/Oncology. 2002 ; Vol. 24, No. 2. pp. 130-133.
@article{a681b45ab926419089ce171b3df7dfc0,
title = "Influence of phenytoin on the disposition of irinotecan: A case report",
abstract = "Irinotecan (CPT-11), a water-soluble topoisomerase I inhibitor, is metabolized by carboxylesterase enzymes to form an active metabolite, SN-38. Recent studies have shown that irinotecan also undergoes oxidative metabolism by the P450 isozyme CYP3A4, leading to the formation of a minor inactive metabolite, 7-ethyl-10-[4-N-[(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). The elucidation of this metabolic pathway suggests the potential for drug interactions when irinotecan is administered with other inducers or substrates of CYP3A4. In this report, the authors summarize the pharmacokinetic profile of irinotecan and its major metabolites with and without concomitant phenytoin administration in an individual patient. These studies revealed that concomitant phenytoin administration resulted in a marked decrease in the systemic exposure to irinotecan and SN-38 and an increase in the exposure to APC. The area under the curve of irinotecan and SN-38 decreased by 63{\%} and 60{\%}, respectively; the area under the curve of APC increased by approximately 16{\%}. Further detailed pharmacokinetic studies of irinotecan in patients receiving concomitant therapy with enzyme-inducing anticonvulsants are required so that rational dosing recommendations can be provided for this patient population.",
keywords = "CYP3A4, Irinotecan, Pharmacokinetics, Phenytoin, SN-38",
author = "Murry, {Daryl J.} and Irene Cherrick and Veronia Salama and Stacey Berg and Mark Bernstein and Nancy Kuttesch and Blaney, {Susan M.}",
year = "2002",
month = "1",
day = "1",
doi = "10.1097/00043426-200202000-00014",
language = "English (US)",
volume = "24",
pages = "130--133",
journal = "Journal of Pediatric Hematology/Oncology",
issn = "1077-4114",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Influence of phenytoin on the disposition of irinotecan

T2 - A case report

AU - Murry, Daryl J.

AU - Cherrick, Irene

AU - Salama, Veronia

AU - Berg, Stacey

AU - Bernstein, Mark

AU - Kuttesch, Nancy

AU - Blaney, Susan M.

PY - 2002/1/1

Y1 - 2002/1/1

N2 - Irinotecan (CPT-11), a water-soluble topoisomerase I inhibitor, is metabolized by carboxylesterase enzymes to form an active metabolite, SN-38. Recent studies have shown that irinotecan also undergoes oxidative metabolism by the P450 isozyme CYP3A4, leading to the formation of a minor inactive metabolite, 7-ethyl-10-[4-N-[(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). The elucidation of this metabolic pathway suggests the potential for drug interactions when irinotecan is administered with other inducers or substrates of CYP3A4. In this report, the authors summarize the pharmacokinetic profile of irinotecan and its major metabolites with and without concomitant phenytoin administration in an individual patient. These studies revealed that concomitant phenytoin administration resulted in a marked decrease in the systemic exposure to irinotecan and SN-38 and an increase in the exposure to APC. The area under the curve of irinotecan and SN-38 decreased by 63% and 60%, respectively; the area under the curve of APC increased by approximately 16%. Further detailed pharmacokinetic studies of irinotecan in patients receiving concomitant therapy with enzyme-inducing anticonvulsants are required so that rational dosing recommendations can be provided for this patient population.

AB - Irinotecan (CPT-11), a water-soluble topoisomerase I inhibitor, is metabolized by carboxylesterase enzymes to form an active metabolite, SN-38. Recent studies have shown that irinotecan also undergoes oxidative metabolism by the P450 isozyme CYP3A4, leading to the formation of a minor inactive metabolite, 7-ethyl-10-[4-N-[(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). The elucidation of this metabolic pathway suggests the potential for drug interactions when irinotecan is administered with other inducers or substrates of CYP3A4. In this report, the authors summarize the pharmacokinetic profile of irinotecan and its major metabolites with and without concomitant phenytoin administration in an individual patient. These studies revealed that concomitant phenytoin administration resulted in a marked decrease in the systemic exposure to irinotecan and SN-38 and an increase in the exposure to APC. The area under the curve of irinotecan and SN-38 decreased by 63% and 60%, respectively; the area under the curve of APC increased by approximately 16%. Further detailed pharmacokinetic studies of irinotecan in patients receiving concomitant therapy with enzyme-inducing anticonvulsants are required so that rational dosing recommendations can be provided for this patient population.

KW - CYP3A4

KW - Irinotecan

KW - Pharmacokinetics

KW - Phenytoin

KW - SN-38

UR - http://www.scopus.com/inward/record.url?scp=0036171737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036171737&partnerID=8YFLogxK

U2 - 10.1097/00043426-200202000-00014

DO - 10.1097/00043426-200202000-00014

M3 - Article

C2 - 11990699

AN - SCOPUS:0036171737

VL - 24

SP - 130

EP - 133

JO - Journal of Pediatric Hematology/Oncology

JF - Journal of Pediatric Hematology/Oncology

SN - 1077-4114

IS - 2

ER -