Differential alteration of drug-metabolizing enzyme activities after cyclophosphamide/adriamycin administration in breast cancer patients.
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.
Elkiran
T
T
Department of Medical Oncology, Institute of Oncology, Faculty of Medicine, Firat University, Turkey. telkiran@yahoo.com
Harputluoglu
H
H
Yasar
U
U
Babaoglu
M O
MO
Dincel
A K
AK
Altundag
K
K
Ozisik
Y
Y
Guler
N
N
Bozkurt
A
A
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
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