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Effect of five structurally diverse H2-receptor antagonists on drug metabolism.
Biochem Pharmacol. 1986 Dec 15; 35(24):4457-61.BP

Abstract

Some H2-receptor antagonists can interact with the biotransformation of other drugs. This is due to their binding to cytochrome P-450. We tested the in vitro effects of 5 different H2-receptor antagonists cimetidine (C), oxmetidine (O), ranitidine (R), famotidine (F) and nizatidine (N) on arylhydrocarbon-hydroxylase, 7-ethoxycoumarin-O-deethylase and 7-ethoxy-resorufin-O-deethylase activity using liver microsomes from man as well as from untreated, phenobarbital and 3-methylcholanthrene treated rats. In addition their binding to human microsomal cytochrome P-450 was evaluated. The in vivo effects of these antagonists were investigated on the hepatic elimination of diazepam in healthy volunteers. In vitro O was found to be the most effective inhibitor of the enzyme activities studied. C showed a clear inhibitory effect only with rat liver microsomes whereas the remaining drugs were more than 10 times less potent. The binding affinities of these antagonists showed a similar tendency: the Ks-values for O, C and R were 0.2, 0.9 and 5.1 mM, respectively; for F and N no binding up to 4 mM could be observed. However, in man, only C inhibited the hepatic elimination of diazepam by about 45% while R, O, N and F did not affect the pharmacokinetics of diazepam. Thus, it could be concluded from our studies that one cannot extrapolate in vitro data of the inhibitory potency of H2-receptor antagonists in every case to human in vivo drug metabolism.

Authors

Pasanen M
No affiliation info available
Arvela P
No affiliation info available
Pelkonen O
No affiliation info available
Sotaniemi E
No affiliation info available
Klotz U
No affiliation info available

MeSH

7-Alkoxycoumarin O-DealkylaseAnimalsAryl Hydrocarbon HydroxylasesBiotransformationCimetidineCytochrome P-450 CYP1A1Cytochrome P-450 Enzyme SystemDiazepamFamotidineHistamine H2 AntagonistsHumansImidazolesKineticsMaleMicrosomes, LiverNizatidineOxidoreductasesOxygenasesPharmaceutical PreparationsRanitidineRatsRats, Inbred StrainsThiazoles

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

2878667

Citation

Pasanen, M, et al. "Effect of Five Structurally Diverse H2-receptor Antagonists On Drug Metabolism." Biochemical Pharmacology, vol. 35, no. 24, 1986, pp. 4457-61.
Pasanen M, Arvela P, Pelkonen O, et al. Effect of five structurally diverse H2-receptor antagonists on drug metabolism. Biochem Pharmacol. 1986;35(24):4457-61.
Pasanen, M., Arvela, P., Pelkonen, O., Sotaniemi, E., & Klotz, U. (1986). Effect of five structurally diverse H2-receptor antagonists on drug metabolism. Biochemical Pharmacology, 35(24), 4457-61.
Pasanen M, et al. Effect of Five Structurally Diverse H2-receptor Antagonists On Drug Metabolism. Biochem Pharmacol. 1986 Dec 15;35(24):4457-61. PubMed PMID: 2878667.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of five structurally diverse H2-receptor antagonists on drug metabolism. AU - Pasanen,M, AU - Arvela,P, AU - Pelkonen,O, AU - Sotaniemi,E, AU - Klotz,U, PY - 1986/12/15/pubmed PY - 1986/12/15/medline PY - 1986/12/15/entrez SP - 4457 EP - 61 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 35 IS - 24 N2 - Some H2-receptor antagonists can interact with the biotransformation of other drugs. This is due to their binding to cytochrome P-450. We tested the in vitro effects of 5 different H2-receptor antagonists cimetidine (C), oxmetidine (O), ranitidine (R), famotidine (F) and nizatidine (N) on arylhydrocarbon-hydroxylase, 7-ethoxycoumarin-O-deethylase and 7-ethoxy-resorufin-O-deethylase activity using liver microsomes from man as well as from untreated, phenobarbital and 3-methylcholanthrene treated rats. In addition their binding to human microsomal cytochrome P-450 was evaluated. The in vivo effects of these antagonists were investigated on the hepatic elimination of diazepam in healthy volunteers. In vitro O was found to be the most effective inhibitor of the enzyme activities studied. C showed a clear inhibitory effect only with rat liver microsomes whereas the remaining drugs were more than 10 times less potent. The binding affinities of these antagonists showed a similar tendency: the Ks-values for O, C and R were 0.2, 0.9 and 5.1 mM, respectively; for F and N no binding up to 4 mM could be observed. However, in man, only C inhibited the hepatic elimination of diazepam by about 45% while R, O, N and F did not affect the pharmacokinetics of diazepam. Thus, it could be concluded from our studies that one cannot extrapolate in vitro data of the inhibitory potency of H2-receptor antagonists in every case to human in vivo drug metabolism. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/2878667/Effect_of_five_structurally_diverse_H2_receptor_antagonists_on_drug_metabolism_ DB - PRIME DP - Unbound Medicine ER -