title: Altered pharmacokinetics and metabolism of CPT-11 in liver dysfunction: a need for guidelines.
abstract: Metabolic conversion of CPT-11 is a major route of elimination of this new topoisomerase 1 inhibitor. Presently, recommendations for dose adjustments of CPT-11 in patients with liver dysfunction are lacking. We describe the case of a patient with metastatic colon cancer with liver dysfunction treated with CPT-11 at two different dose levels (100 mg/m2 and 30 mg/m2, single dose, administered as a 90-min i.v. infusion). The lactones and carboxylates of CPT-11 and SN-38 were determined by high-performance liquid chromatography. SN-38 glucuronide was determined after deglucuronidation. The procedures allowed intrapatient comparison of pharmacokinetics and metabolism of the drug. Severe side effects were encountered, which could be explained by the reduced clearance of CPT-11 and its metabolites. These included neutropenic fever with culture-proven septicemia, thrombocytopenia, somnolence, diarrhea, and signs and symptoms of transient hepatic failure. Our findings offer important data for the further development of guidelines for dose reduction of CPT-11 in patients with liver dysfunction.
authors.affiliation: Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: van Groeningen
authors.forename: W J
authors.initials: WJ
authors.lastname: Van der Vijgh
authors.forename: J J
authors.initials: JJ
authors.lastname: Baars
authors.forename: H
authors.initials: H
authors.lastname: Stieltjes
authors.forename: K
authors.initials: K
authors.lastname: Huibregtse
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008107:Liver Diseases / Q000150:complications / Q000503:physiopathology*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D012890:Sleep / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin