Effect of H2-receptor antagonists on the pharmacokinetics of 5-fluorouracil in the rat and monkey.
The effect of short term (7 days) and long term (28 days) pretreatment with the imidazole H2-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 t1/2.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 H2-receptor antagonist, ranitidine, caused no significant effect on 5-FUra kinetics. In the monkey, 7 days pretreatment with CMT increased t1/2.z by 32 per cent leaving other 5-FUra kinetic parameters unchanged; 28 days pretreatment increased both t1/2.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 H2-receptor blockade is administered concurrently with 5-FUra that a non-imidazole based H2-receptor antagonist such as RNT should be substituted for CMT.
Department of Therapeutics, Charing Cross and Westminster Medical School, London.
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Dilloway
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Lant
D000818:Animals; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006207:Half-Life; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008252:Macaca fascicularis; D009249:NADP / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011899:Ranitidine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D006635:Histamine H2 Antagonists; D009249:NADP; D002927:Cimetidine; D011899:Ranitidine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil