RGD Reference Report - Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats.

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Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats.
Authors:	Kobuchi, S Ito, Y Okada, K Imoto, K Takada, K
Citation:	Kobuchi S, etal., Eur J Drug Metab Pharmacokinet. 2013 Sep;38(3):171-81. doi: 10.1007/s13318-012-0114-9. Epub 2012 Nov 30.
RGD ID:	11251746
Pubmed:	PMID:23197286 (View Abstract at PubMed)
DOI:	DOI:10.1007/s13318-012-0114-9 (Journal Full-text)
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 mug h mL(-1), 0.30 +/- 0.02 h, respectively) were significantly lower than that in control rats (13.46 +/- 1.20 mug h mL(-1), 0.52 +/- 0.05 h, respectively), whereas total plasma clearance (CLtot) 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 CLtot 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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
colorectal cancer		ISO	Dpyd (Rattus norvegicus)	11251746; 11251746	protein:increased activity:liver	RGD
colorectal cancer		IDA		11251746	protein:increased activity:liver	RGD

Objects Annotated

Genes (Rattus norvegicus)

Dpyd (dihydropyrimidine dehydrogenase)

Genes (Mus musculus)

Dpyd (dihydropyrimidine dehydrogenase)

Genes (Homo sapiens)

DPYD (dihydropyrimidine dehydrogenase)

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Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats.