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Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats.
MedLine Citation:
PMID:  23197286     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine-induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration-time curve (AUC) and elimination half-life (t (1/2)) in CRC rats (10.02 ± 0.37 μg h mL(-1), 0.30 ± 0.02 h, respectively) were significantly lower than that in control rats (13.46 ± 1.20 μg h mL(-1), 0.52 ± 0.05 h, respectively), whereas total plasma clearance (CL(tot)) in CRC rats (2.01 ± 0.07 L h(-1) kg(-1)) was significantly increased compared with that in control rats (1.54 ± 0.14 L h(-1) kg(-1)). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20 % lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC and t (1/2) and an increase in CL(tot) after 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.
Authors:
Shinji Kobuchi; Yukako Ito; Kae Okada; Kazuki Imoto; Kanji Takada
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-30
Journal Detail:
Title:  European journal of drug metabolism and pharmacokinetics     Volume:  -     ISSN:  0378-7966     ISO Abbreviation:  Eur J Drug Metab Pharmacokinet     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7608491     Medline TA:  Eur J Drug Metab Pharmacokinet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8412, Japan, ky05122@poppy.kyoto-phu.ac.jp.
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