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

Abstract

Cyclophosphamide (CPA) and adriamycin (ADR) are widely used chemotherapeutics. It has been reported that CPA and ADR singly or in combination could alter the activities of a variety of drug metabolizing enzymes in rats. The effects of CPA/ADR in drug metabolism in human are largely unknown. Caffeine is a probe agent to assess the metabolic activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO), and losartan is a marker for determination of CYP2C9 activity. This study aimed to investigate the effects of CPA/ADR combination treatment on drug-metabolizing enzymes by using these probes. A single oral dose of 25 mg losartan and a cup of instant coffee was given to 15 breast cancer patients at three occasions: two days before, after 2–4 hours and after three weeks of the first cycle of adjuvant CPA/ADR chemotherapy. Losartan, caffeine and their metabolites were analyzed by using HPLC. Mean CYP1A2 activity (range) was markedly increased by about 20% (−89% – 126%) and CYP2C9 activity decreased by 315%(−21% – 2214%) three weeks after the administration of CPA/ADR chemotherapy (p=0.05). There were no acute or chronic effects of the CPA/ADR administration on CYP2A6, NAT2 or XO activities. These results suggest that treatment with chemotherapeutics may exert differential effects on drug metabolizing enzyme activities in human.

(Supported by TUBITAK-SBAG COST B25-105S027 and UY/TUBA-GEBIP/2005-17)