Document Detail


The physiological disposition of the uricosuric-saluretic agent (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196) in the rat, dog, and monkey.
MedLine Citation:
PMID:  10149     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The physiological disposition of a new saluretic-uricosuric agent, (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196), was studied in the rat, dog, and monkey. MK-196 was well absorbed and showed minimal metabolism in these species. Peak plasma levels of radioactivity and drug occurred 0.5-2 hr after oral administration at a dose of 2.5 mg/kg. Essentially all of the radioactivity present in the plasma during the first day was intact MK-196. Following a single dose, a long terminal half-life for plasma radioactivity was observed in the dog (approximately 68 hr) and monkey (approximately 105 hr). The chronic administration of MK-196 to dogs resulted in a dose-related plasma profile and showed no tendency to increase or decrease with dosing. However, upon repeated drug administration to monkeys, the plasma levels of drug increased and then decreased, possibly due to hypochloremia and secondary metabolic alkalosis. Fecal excretion was the predominant route of tracer elimination in the dog (approximately 80%) and rat (approximately 94%), whereas the monkey eliminated the majority of the dose (approximately 60%) via the urine. Minimal metabolism was noted in the three lower species; most of the urinary, plasma, and fecal radioactivity was accounted for as intact drug and its glucuronide conjugate. Three minor metabolites, which were present in dog bile, plasma, and urine, were characterized as: (l,7-dichloro-1alpha-hydroxy-2-methyl-2-phenyl-5-indanyloxy)acetic acid, I; (6,7-dichloro-2-(4-hydroxyphenyl)-2-methyl-2-oxo-5-indanyloxy)acetic acid, II; and 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone, III. The monkey urine and plasma also contained small amounts of II.
Authors:
A G Zacchei; T I Wishousky
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  4     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:    1976 Sep-Oct
Date Detail:
Created Date:  1977-01-03     Completed Date:  1977-01-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  490-8     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Animals
Chromatography, Gas
Diuretics / administration & dosage,  metabolism*
Dogs
Drug Administration Schedule
Female
Half-Life
Haplorhini
Indans / administration & dosage,  metabolism*
Indenes / metabolism*
Infusions, Parenteral
Kinetics
Macaca mulatta
Male
Mass Spectrometry
Rats
Species Specificity
Uricosuric Agents / administration & dosage,  metabolism*
Chemical
Reg. No./Substance:
0/Diuretics; 0/Indans; 0/Indenes; 0/Uricosuric Agents

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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