Effect of low-dose phenobarbitone on five indirect indices of hepatic microsomal enzyme induction and plasma lipoproteins in normal subjects.

marked fall in the association constant for diazepam in the presence of valproic acid: Ka = 8.9 x 104 M-1 (diazepam only); Ka = 4.1 x 104 M-1 (diazepam and valproic acid). The results suggest that diazepam, under the conditions used, has one primary binding site on human serum albumin. This is in agreement with the findings of previous authors (Muller & Wollert, 1973; Kober et al., 1979). The inhibition of diazepam binding by valproic acid has been shown to be competitive since the number of binding sites for diazepam remained unchanged while the affinity of diazepam for these sites was reduced. The disposition kinetics of many drugs can be influenced by changes in plasma protein binding. Diazepam is a drug subject to restrictive elimination by hepatic metabolism and it has been shown that for such drugs the total clearance is directly proportional to the free fraction of the drug (Shand, Mitchell & Oates, 1975). Changes in diazepam free fraction may therefore cause an important alteration in disposition. We thank the National Fund for Research into Crippling Diseases for financial support.