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)
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