Genetic control of dicumarol levels in man.
The mean half-life of dicumarol in the plasma of seven sets of identical and seven sets of fraternal twins after a single oral dose of 4 mg/kg was 43.6+/-SD 17.9 hr. Half-lives ranged from 7 to 74 hr in these 28 normal adults not receiving other drugs for 2 wk preceding dicumarol administration. Large differences among unrelated individuals in dicumarol half-life disappeared almost completely in identical twins, but persisted to some extent in most sets of fraternal twins. These results indicate that marked differences among subjects in dicumarol half-life are under genetic rather than environmental control. Reproducibility of values for dicumarol half-life was demonstrated. A direct relationship between the dose and the half-life of dicumarol occurred in unrelated volunteers administered progressively larger doses at 10-day intervals. Dose dependence of the half-life of a drug results in increased variability of half-life and hence in greater risks of toxicity on long-term therapy. Risks of toxicity on the one hand and of failure to anticoagulate adequately on the other can be reduced by determining dicumarol half-life before starting long-term therapy. Half-lives for dicumarol and phenylbutzone tended to be correlated in the 28 twins, but no correlation occurred between dicumarol and antipyrine half-lives.
D000328:Adult; D000983:Antipyrine / Q000097:blood; D002110:Caffeine; D002498:Centrifugation; D003069:Coffee; D001728:Dicumarol / Q000097:blood*; D005260:Female; D005826:Genetics, Medical; D006801:Humans; D008297:Male; D008748:Methylcholanthrene; D008875:Middle Aged; D009538:Nicotine; D010653:Phenylbutazone / Q000097:blood; D011247:Pregnancy; D011517:Prothrombin Time; D012907:Smoking; D013053:Spectrophotometry; D014427:Twins
D003069:Coffee; D002110:Caffeine; D008748:Methylcholanthrene; D009538:Nicotine; D001728:Dicumarol; D010653:Phenylbutazone; D000983:Antipyrine