Effects of 5-Fluorouracil on the Drug-Metabolizing Enzymes of the Small Intestine and the Consequent Drug Interaction with Nifedipine in Rats
- Pharmacokinetics Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
Abstract
5-Fluorouracil (5-FU) is a widely used antineoplastic agent. 5-FU therapy often causes gastrointestinal toxicity, which is suppressed by concomitant administration of potassium oxonate (Oxo). Here, we investigated the effect of 5-FU on the small-intestinal drug-metabolizing enzymes, which play important roles in the first-pass metabolism of drugs, in rats, by enzyme measurements and immunoblot analyses. During repeated administration of a combination of 1-(2-tetrahydrofuryl)-5-fluorouracil, an oral 5-FU-derivative drug, and 5-chloro-2,4-dihydroxypyridine (FCD), an inhibitor of 5-FU degradation, the activities of 7-ethoxyresorufin-O-deethylase, testosterone 6β-hydroxylase, 4-methylumbelliferone UDP-glucuronyltransferase, and 1-chloro-2,4-dinitrobenzene glutathioneS-transferase decreased significantly on day 4, and the activity of NADPH-cytochrome P450 (CYP) reductase decreased significantly on day 7. These effects were found to be attributable to a reduction in the enzyme protein contents in the small-intestinal mucosa. The enzymatic alterations significantly increased the plasma concentrations of orally administered nifedipine, which was prevented by concomitant administration of Oxo with FCD. However, consecutive administration of FCD for 4 days did not cause any alterations in the activity of the hepatic CYP isozyme-supported testosterone hydroxylase. These results suggest that continuous exposure to 5-FU leads to a decrease in the activities of drug-metabolizing enzymes in the intestinal mucosa by decreasing their enzyme protein contents, and increases the plasma concentrations of orally administered nifedipine, and that the sensitivity of these enzymes to the drug is greater than that of the enzymes of the liver. These effects were prevented by concomitant administration of Oxo.
Footnotes
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Send reprint requests to: Dr. Kunihiro Yoshisue, Pharmacokinetics Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan. E-mail: kuni-yosisue{at}taiho.co.jp
- Abbreviation:
- 5-FU
- 5-fluorouracil
- GI
- gastrointestinal
- TS
- thymidylate synthase
- DPD
- dihydropyrimidine dehydrogenase
- FT
- 1-(2-tetrahydrofuryl)-5-fluorouracil
- CDHP
- 5-chloro-2,4-dihydroxypyridine
- FCD
- a mixture of FT and CDHP at a molar ratio of 1:0.4
- Oxo
- 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6-carboxylate
- FCD + Oxo
- a mixture of FT, CDHP, and Oxo at a molar ratio of 1:0.4:1
- CYP
- cytochrome P450
- CDNB
- 1-chloro-2,4-dinitrobenzene
- 4-MU
- 4-methylumberiferone
- PEG
- polyethylene glycol 4000
- APMSF
- (p-amidinophenyl)methylsulfonyl fluoride
- PVDF
- polyvinylidene difluoride
- HPLC
- high-performance liquid chromatography
- EDTA
- ethylenediamine-N,N,N′,N′-tetraacetic acid
- UGT
- UDP-glucuronyltransferase
- EROD
- 7-ethoxyresorufin-O-deethylase
- GST
- glutathioneS-transferase
- PBS-T
- phosphate-buffered saline (pH 7.5) containing 0.1% (v/v) Tween 20
- AUC
- area under the plasma concentration-time curve from time 0 to infinity
- t1/2
- half-life of elimination
- CL
- total body clearance
- Cmax
- maximum concentration
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- Received November 29, 2000.
- Accepted February 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
