Document Detail

Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats.
MedLine Citation:
PMID:  529027     Owner:  NLM     Status:  MEDLINE    
The interaction of phenylbutazone with the enantiomers and racemic [3H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 microgram/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(-), and R, S(+/-) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenylbutazone. For racemic [oH]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration--effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration--response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.
W Schmidt; E Jähnchen
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of pharmacokinetics and biopharmaceutics     Volume:  7     ISSN:  0090-466X     ISO Abbreviation:  J Pharmacokinet Biopharm     Publication Date:  1979 Dec 
Date Detail:
Created Date:  1980-04-23     Completed Date:  1980-04-23     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0357115     Medline TA:  J Pharmacokinet Biopharm     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  643-63     Citation Subset:  IM    
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MeSH Terms
4-Hydroxycoumarins / pharmacology*
Drug Interactions
Liver / metabolism
Phenprocoumon / blood,  pharmacology*
Phenylbutazone / blood,  pharmacology*
Prothrombin / metabolism
Reg. No./Substance:
0/4-Hydroxycoumarins; 0/Anticoagulants; 435-97-2/Phenprocoumon; 50-33-9/Phenylbutazone; 9001-26-7/Prothrombin

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

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