Kinetics of drug-drug interactions

Since many drug-drug pharmacokinetic interactions are dependent on the concentrations of the interacting species, the degree of interaction should be a graded phenomenon varying with drug and/or metabolite concentration and thus drug administration and time. Hence one should be able to develop predictive kinetic models for such interactions. A change in drug plasma levels when a compound is administered as a single dose together with another drug can arise from a change drug clearance, displacement from binding sites, a change in elimination rates, or a combination of any or all of these possibilities. The interaction of phenobarbital and the sparingly soluble oral antifungal agent, griseofulvin, is one example. Analysis shows that there is no change in elimination half- life of griseofulvin but that phenobarbital reduces the extent of griseofulvin absorption rather than enhances its elimination. Sulfaphenazole inhibits the metabolism and markedly prolongs tolbutamide plasma levels. An anticipated sudden drop in the excretion rate of the tolbutamide metabolites at maximum sulfonamide plasma levels is associated with an almost complete block of tolbutamide oxidation. The inhibitor constant K₁for this interaction has been calculated, allowing one to predict tolbutamide and metabolite levels when the inhibitor is administered. Drug- drug interaction resulting from protein displacement has been hypothesized by a number of authors. However, the potentiation of the anticoagulant warfarin in patients receiving phenylbutazone is more complicated than has been envisioned previously. While displacement occurs, data suggest that phenylbutazone primarily acts through selective inhibition to alter the isomeric composition and potency of the racemic warfarin administered. The warfarin- phenylbutazone interaction study stresses the importance of measuring metabolites as well as intact drug.Much of the work reported in this paper was supported by a grant from the National Institutes of Health, Bethesda, Maryland, NIGMS 16496.This paper was presented by Dr. Rowland at the Conference on Pharmacology and Pharma-cokinetics; Problems and Perspectives, October 30–November 1, 1972, at the Fogarty International Center, National Institutes of Health, Bethesda, Maryland. This paper, in a slightly different format, will be published in the Proceedings of the Conference by Plenum Press, New York.