Pharmacodynamic analysis between plasma level and inhibition of acid output after administration of a new histamine H2-receptor antagonist (Z-300) in dog.
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 approximately 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 approximately 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.
Furuta
S
S
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, Saitama, Japan.
Sugimoto
T
T
Suzuki
M
M
Yoneta
T
T
Hori
Y
Y
Morita
H
H
Aita
H
H
Sano
H
H
D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects; D013454:Sulfoxides / Q000097:blood; D013997:Time Factors
D000081:Acetamides; D006635:Histamine H2 Antagonists; D010880:Piperidines; D013454:Sulfoxides; C077871:Z 300