부산대학교 도서관

BACKGROUND AND OBJECTIVES: Dihydropyrimidine dehydrogenase (DPD) plays a key role in the catabolism of 5-fluorouracil (5-FU) to 5-fluoro-5,6-dihydrouracil (5-FDHU), and as such, an impairment of DPD has been recognized as an important factor for altered 5-FU and 5-FDHU pharmacokinetics, predisposing patients to the development of severe 5-FU–associated toxicity. Our objectives were to avoid severe 5-FU toxicities in patients with greatly impaired 5-FU and 5-FDHU pharmacokinetics after the administration of a reduced test dose of 5-FU and to investigate possible 5-FU or 5-FDHU pharmacokinetic parameters of the test dose related to the most common drug toxicities that affect patients after the first cycle of 5-FU chemotherapy. METHODS: Pharmacokinetics of 5-FU/5-FDHU and DPD activity in peripheral blood mononuclear cells (PBMCs) were examined in 188 gastrointestinal cancer patients given a test dose of 5-FU, 250 mg/m, 2 weeks before starting the planned 5-FU treatment of 370 mg/m plus L-folinic acid, 100 mg/m, for 5 days every 4 weeks. Drug levels were examined by HPLC, and toxicities were graded according to World Health Organization criteria. RESULTS: The 5-FU test dose was well tolerated in all patients. Of 188 patients, 3 (1.6%) had marked alterations of 5-FU/5-FDHU pharmacokinetics (ie, 5-FU half-life [t½β] >5 hours, 5-FU total body clearance [CLTB] <1 L · h · m, and 5-FDHU time to reach maximum plasma concentration [tmax] ≥45 minutes); they were excluded from 5-FU treatments and treated with irinotecan, which was well tolerated. The plasma disposition of 5-FU in the remaining 185 patients revealed an area under the curve (AUC) of 3.73 ± 2.18 h · μg/mL (mean ± SD), maximum plasma concentration (Cmax) of 16.78 ± 8.61 μg/mL, and t½β of 0.16 ± 0.15 hour, whereas the CLTB was 65.67 ± 31.86 L · h · m. The 5-FDHU plasma profile showed a Cmax value of 3.64 ± 1.94 μg/mL, whereas the tmax value was 26.63 ± 10.06 minutes, with an AUC value of 3.71 ± 1.90 h · μg/mL. The PBMC DPD activity was 202.15 ± 141.14 pmol 5-FDHU · min · mg protein (95% confidence interval, 165–239.3 pmol 5-FDHU · min · mg protein). A significant correlation between 5-FU AUC and 5-FDHU AUC was found (r = 0.5492, P < .0001), whereas a weaker correlation between PBMC DPD activity and both 5-FDHU AUC (r = 0.328, P = .0121) and 5-FDHU Cmax (r = 0.369, P = .0044) was found. Interestingly, no relationships between PBMC DPD activity and common toxicities were found, whereas 5-FDHU tmax values greater than 30 minutes were associated with the risk of moderate to severe neutropenia and diarrhea (P = .0323 and P = .0138, respectively; chi-square test). CONCLUSIONS: This study suggests a successful approach for preventing severe or life-threatening toxicities in gastrointestinal cancer patients who are candidates for standard 5-FU treatment by analyzing the 5-FU and 5-FDHU pharmacokinetic parameters after the administration of a reduced 5-FU test dose.