Abstract
S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.
Footnotes
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This work was supported in part by a grant-in-aid for Cancer Research [Grant 17-8]; a Health and Labour Sciences Research grant from the Ministry of Health, Labour and Welfare of Japan (2005-Clinical Cancer Research-008); a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science [Grant A-16200038]; and a grant from the Japan Research Foundation for Clinical Pharmacology.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027052.
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ABBREVIATIONS: CDHP, 5-chloro-2,4-dihydroxypyridine; 5-FU, 5-fluorouracil; DPD, dihydropyrimidine dehydrogenase; AUC, area under the concentration-time curve; Ccr, creatinine clearance.
- Accepted April 21, 2009.
- Received February 6, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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