Pharmacodynamic analysis between plasma level and inhibition of acid output after administration of a new histamine H2-receptor antagonist (Z-300) in dog

• Published in: Xenobiotica Vol. 30; no. 2; pp. 193 - 199
• Main Authors: Furuta, S., Sugimoto, T., Suzuki, M., Yoneta, T., Hori, Y., Morita, H., Aita, H., Sano, H.
• Format: Journal Article
• Language: English
• Published: London Informa UK Ltd 2000; Taylor & Francis
• Subjects: Acetamides - pharmacokinetics; Acetamides - pharmacology; Animals; Biological and medical sciences; Dogs; Gastric Acid - metabolism; Histamine and antagonists. Allergy; Histamine H2 Antagonists - pharmacokinetics; Histamine H2 Antagonists - pharmacology; Male; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Piperidines - pharmacokinetics; Piperidines - pharmacology; Stomach - drug effects; Sulfoxides - blood; Time Factors; Fissipedia; Stomach; Carnivora; Intravenous administration; Secretion; Oral administration; Antihistaminic; Biological activity; Vertebrata; Chemotherapy; Mammalia; Treatment; Acids; Animal; Dog; Antiacid; H2 Histamine receptor
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/004982500237776

1. The relationship between plasma levels of a new H2-receptor antagonist, Z-300, and an active sulphoxide metabolite, and inhibitory effects on gastric acid secretion after intravenous or oral administration to dog have been examined. After both routes of administration, Z-300 in plasma eliminated with two phases, and the terminal half-lives were 2 h. The level of sulphoxide in plasma reached a maximum at 0.6-0.7 h after administration, then subsequently eliminated with a half-life of 6 h. 2. The maximal pharmacological effect of inhibition of gastric acid secretion (90-91%) was observed at 2 h (i.v.) and 6 h (p.o.), and the action persisted until 7 h after administration. 3. Since there was no correlation between plasma levels of Z-300 and pharmacological effects, the pharmacological effects were calculated by pharmacodynamic model including the effect compartment. The inhibition of acid output could be calculated by the amounts of Z-300 and sulphoxide corrected by pharmacological efficacy in the effect compartment. 4. These findings suggest that Z-300 contributes to the rapid appearance of the pharmacological effects in dog, whereas the sulphoxide, which eliminates slowly in plasma, contributes to duration.