Effects of 5-fluorouracil on the drug-metabolizing enzymes of the small intestine and the consequent drug interaction with nifedipine in rats.
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 6beta-hydroxylase, 4-methylumbelliferone UDP-glucuronyltransferase, and 1-chloro-2,4-dinitrobenzene glutathione S-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.
Yoshisue
K
K
Pharmacokinetics Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan. kuni-yosisue@taiho.co.jp
Nagayama
S
S
Shindo
T
T
Kawaguchi
Y
Y
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005472:Fluorouracil / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D015151:Immunoblotting; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D010094:Oxonic Acid / Q000008:administration & dosage; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D005641:Tegafur / Q000008:administration & dosage
D000964:Antimetabolites, Antineoplastic; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D011725:Pyridines; D005641:Tegafur; D010094:Oxonic Acid; D003577:Cytochrome P-450 Enzyme System; C113764:Cyp2c13 protein, rat; D019363:Cytochrome P-450 CYP1A1; D009251:NADPH-Ferrihemoprotein Reductase; D014453:Glucuronosyltransferase; D010430:Pentosyltransferases; C022500:pyrimidine phosphoribosyltransferase; D005982:Glutathione Transferase; D009543:Nifedipine; D005472:Fluorouracil; C104201:gimeracil