Relationship between dicumarol distribution and the effect of enzyme induction on dicumarol elimination in rats.
Pronounced intersubject differences in the apparent first-order elimination rate constant (kapp) for dicumarol in rats have been found to be due to corresponding differences in the distribution of dicumarol between the liver (the site of dicumarol biotransformation) and the rest of the body. From theoretical considerations and experimental results in animals given only dicumarol, it has been shown that kapp is linearly related to the fraction of drug in the liver (FL). The proportionality constant (k) for these variables was defined as the intrinsic elimination rate constant for dicumarol which should reflect the activity of the enzyme system(s) involved in the elimination of this drug. The purpose of this investigation was to determine the effect of enzyme induction on dicumarol distribution and on the relationship between kapp and FL in rats. It was found that pretreatment with phenobarbital caused a substantial increase in kapp, but that it had no apparent effect on the serum/liver and serum/kidney concentration ratios of dicumarol. The relative weight of the liver was significantly increased by phenobarbital treatment but the weight of the kidneys was not affected. Linear relationships between kapp and FL were found for both the control and the phenobarbital treated groups, but with a significant difference in the slopes of the regression lines. This study illustrates the application of a pharmacokinetic technique which permits a clear and quantitative distinction between the relative contributions of enzyme activity and body distribution to the in vivo elimination kinetics of a drug.
D000818:Animals; D001728:Dicumarol / Q000097:blood / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D001728:Dicumarol; D010634:Phenobarbital