title: Differential alteration of drug-metabolizing enzyme activities after cyclophosphamide/adriamycin administration in breast cancer patients.
abstract: Cyclophosphamide (CPA) and adriamycin (ADR) are widely used drugs for cancer chemotherapy. It has been reported that CPA and ADR singly or in combination could alter activities of a variety of drug-metabolizing enzymes in animals via multiple mechanisms. However, the effects of CPA/ADR on drug metabolism are largely unknown in human beings. Losartan metabolism has been suggested as a marker for determination of CYP2C9 activity. Caffeine is a commonly used probe to assess the metabolic activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO). The present study was designed to analyze the effects of CPA/ADR on these drug-metabolizing enzymes by using losartan and caffeine as probe drugs. A single oral dose of 25 mg losartan and a cup of instant coffee was given to 15 breast cancer patients on three occasions (before, and 2-4 h and 3 weeks after the adjuvant CPA/ADR chemotherapy [600 mg CPA/m2/day, 60 mg ADR/m2/day]). Losartan, caffeine and their metabolites were analyzed by using high-pressure liquid chromatography. When compared with baseline, CYP1A2 activity was increased by 20% and CYP2C9 activity was decreased by 315% 3 weeks after the administration of CPA/ADR chemotherapy (p = 0.05). The chemotherapy did not change the activities of CYP2A6, NAT2 or XO. CPA/ADR treatment caused a differential effect on drug-metabolizing enzyme activities, and this may contribute to predicting the efficacy and toxicity of chemotherapeutics, as well as understanding the drug-drug interactions.
authors.affiliation: Department of Medical Oncology, Institute of Oncology, Faculty of Medicine, Firat University, Turkey. telkiran@yahoo.com
authors.forename: T
authors.initials: T
authors.lastname: Elkiran
authors.forename: H
authors.initials: H
authors.lastname: Harputluoglu
authors.forename: U
authors.initials: U
authors.lastname: Yasar
authors.forename: M O
authors.initials: MO
authors.lastname: Babaoglu
authors.forename: A K
authors.initials: AK
authors.lastname: Dincel
authors.forename: K
authors.initials: K
authors.lastname: Altundag
authors.forename: Y
authors.initials: Y
authors.lastname: Ozisik
authors.forename: N
authors.initials: N
authors.lastname: Guler
authors.forename: A
authors.initials: A
authors.lastname: Bozkurt
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy; D002110:Caffeine / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065729:Cytochrome P-450 CYP2C9; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019808:Losartan / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism; D011446:Prospective Studies; D014969:Xanthine Oxidase / Q000187:drug effects / Q000378:metabolism
chemical_list: D002110:Caffeine; D004317:Doxorubicin; D003520:Cyclophosphamide; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D014969:Xanthine Oxidase; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D019808:Losartan