N A Helsby1, W Y Lo, P Thompson, G R Laking. 1. Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. n.helsby@auckland.ac.nz
Abstract
PURPOSE: To report a case of altered CYP2C19 metaboliser status following 5-fluorouracil treatment. METHODS: A 78-year-old male with stage III colorectal adenocarcinoma was prescribed with weekly iv 5-fluorouracil and folinic acid (FU/FA). Fourteen weeks after starting FU/FA, the patient was enrolled in a clinical study to investigate the role of tumour burden on drug metabolising enzyme activity. CYP2C19 genotype was determined and the activity of CYP2C19 was measured using proguanil (PG) as a probe substrate. A metabolic ratio (PG/CG) for CYP2C19 activity was determined on three separate occasions, 7 days apart. RESULTS: The patient was homozygous wild type (CYP2C19*1/*1), and on the first test, the metabolic ratio was concordant with the extensive metaboliser genotype. However, at day 14 and day 21, the metabolic capacity of this enzyme had decreased, and the subject had become a poor metaboliser (PG/CG > 30). The patient developed grade III hand and foot syndrome at day 10 of the study during the period of null CYP2C19 activity. CONCLUSIONS: Although 5FU is not a substrate for hepatic drug metabolising CYP enzymes, it may interfere with the synthesis of CYP2C19. Decreased activity of a related enzyme, CYP2C9, following 5FU has been reported previously. Down regulation of CYP2C9 and CYP2C19 synthesis by 5FU therapies may explain the adverse effect of 5FU on the clinical disposition of warfarin and phenytoin.
PURPOSE: To report a case of altered CYP2C19 metaboliser status following 5-fluorouracil treatment. METHODS: A 78-year-old male with stage III colorectal adenocarcinoma was prescribed with weekly iv 5-fluorouracil and folinic acid (FU/FA). Fourteen weeks after starting FU/FA, the patient was enrolled in a clinical study to investigate the role of tumour burden on drug metabolising enzyme activity. CYP2C19 genotype was determined and the activity of CYP2C19 was measured using proguanil (PG) as a probe substrate. A metabolic ratio (PG/CG) for CYP2C19 activity was determined on three separate occasions, 7 days apart. RESULTS: The patient was homozygous wild type (CYP2C19*1/*1), and on the first test, the metabolic ratio was concordant with the extensive metaboliser genotype. However, at day 14 and day 21, the metabolic capacity of this enzyme had decreased, and the subject had become a poor metaboliser (PG/CG > 30). The patient developed grade III hand and foot syndrome at day 10 of the study during the period of null CYP2C19 activity. CONCLUSIONS: Although 5FU is not a substrate for hepatic drug metabolising CYP enzymes, it may interfere with the synthesis of CYP2C19. Decreased activity of a related enzyme, CYP2C9, following 5FU has been reported previously. Down regulation of CYP2C9 and CYP2C19 synthesis by 5FU therapies may explain the adverse effect of 5FU on the clinical disposition of warfarin and phenytoin.