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Effect of H 2 ‐receptor antagonists on the pharmacokinetics of 5‐fluorouracil in the rat and monkey
Author(s) -
Dilloway Mark R.,
Lant F.
Publication year - 1991
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510120103
Subject(s) - cimetidine , pharmacokinetics , pharmacology , dihydropyrimidine dehydrogenase , chemistry , antagonist , toxicity , receptor antagonist , ranitidine , fluorouracil , drug interaction , receptor , kinetics , endocrinology , medicine , biochemistry , chemotherapy , thymidylate synthase , physics , quantum mechanics
The effect of short term (7 days) and long term (28 days) pretreatment with the imidazole H 2 ‐receptor antagonist, cimetidine (CMT), on the pharmacokinetics of 5‐fluorouracil (5‐FUra) has been studied in the rat and cynomolgus monkey. Short‐term pretreatment of rats with CMT significantly increased t 1/2,z by 29 per cent and AUC by 40 per cent: total body clearance was decreased by 30 per cent. Long‐term pretreatment exaggerated these effects. By contrast, short‐ and long‐term pretreatment with the furan H 2 ‐receptor antagonist, ranitidine, caused no significant effect on 5‐FUra kinetics. In the monkey, 7 days pretreatment with CMT increased t 1/2,z by 32 per cent leaving other 5‐FUra kinetic parameters unchanged; 28 days pretreatment increased both t 1/2,z by 41 per cent and AUC by 100 per cent with a decrease in total body clearance of 5‐FUra of 48 per cent. CMT, but not RNT, inhibited cytosolic dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5‐FUra catabolism. It is proposed that the observed effects of CMT on 5‐FUra kinetics are the result of inhibition of DPD. This interaction has the potential for increasing systemic drug toxicity and it is therefore advisable that where H 2 ‐receptor blockade is administered concurrently with 5‐FUra that a non‐imidazole based H 2 ‐receptor antagonist such as RNT should be substituted for CMT.