Differential alteration of drug-metabolizing enzyme activities after cyclophosphamide/adriamycin administration in breast cancer patients


Elkiran T., Harputluoglu H., Yasar U., BABAOĞLU M. Ö. , Dincel A., Altundag K., ...More

Methods and Findings in Experimental and Clinical Pharmacology, vol.29, no.1, pp.27-32, 2007 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 29 Issue: 1
  • Publication Date: 2007
  • Doi Number: 10.1358/mf.2007.29.1.1074690
  • Journal Name: Methods and Findings in Experimental and Clinical Pharmacology
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.27-32
  • Keywords: adriamycin, cyclophosphamide, cytochrome P450, induction, inhibition, IN-VIVO, LOSARTAN OXIDATION, HUMAN CYP2B6, CAFFEINE, CYTOCHROME-P450, BIOTRANSFORMATION, RAT, PHARMACOKINETICS, INHIBITION, ADRIAMYCIN

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. © 2007 Prous Science. All rights reserved.