1. The binding of racemic mixtures of warfarin and warfarin-alcohol to human serum albumin (HSA) is accompanied by an increase in the fluorescence quantum yield of these compounds. This property has been used to measure the characteristics of the binding of warfarin and warfarin-alcohol to HSA at 22 degrees C and 37 degrees C. Within the limits of the technique, no significant differences between the number of binding sites and strength of binding at the tight site at either temperature were observed. 2. The fluorescence of warfarin and warfarin-alcohol was used to label their binding site on HSA and to study the effects of other drugs on their binding. The results indicate that these two molecules are bound to the same site on HSA. 3. The validity of using changes in the fluorescence of warfarin as a measure of its displacement from HSA was investigated. Good correlations were observed between drug-induced decreases in the fluorescence of bound warfarin and displacement as measured by equilibrium dialysis. The displacement of warfarfin, as detected by fluorescence, correlates well with the increase in free warfarin resulting from addition of therapeutic drug concentrations to undiluted human serum. 4. The most potent displacing agents, by all the methods used, were iophenoxic acid, phenylbutazone and oxyphenylbutazone. The first of these is no longer used clinically, but the latter two are and have been reported to cause hypoprothrominaemia by displacing warfarin from HSA. The present study indicates that changes in the fluorescence of warfarin bound to HSA can be used to measure displacement of bound warfarin and to screen drugs that may cause clinically significant interactions by this mechanism.

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Summary: 5‐Fluorocytosine (5‐FC) represents an important advance in the chemotherapy of cryptococcosis and some serious fungal diseases, especially systemic moniliasis. The drug is excreted mainly by the kidney and has a wide margin of safety, but potentially toxic high plasma levels follow normal dosage regimes in patients with renal insufficiency. Using 5‐fluorocytosine‐2‐14C, the plasma and urinary clearances of 5‐FC have been measured together with simultaneous inulin clearances. In eight healthy subjects we have demonstrated that the drug is eliminated largely by the kidney, an average of 90% of an intravenous load being recovered as unchanged drug in the urine within 48 hours. Following the intravenous load, the fall in plasma concentration is exponential with a half‐time of 234.6 ‡24.8 minutes (SE). The drug is distributed widely in the body and not bound to plasma proteins. Evidence was obtained that 5‐FC is excreted by filtration at the glomerulus without significant tubular reabsorption or secretion. Clearances calculated from the exponential plasma decay curves are greater than clearances calculated by standard methods from plasma concentration and urinary excretion rate, suggesting that some of the clearance from plasma is not due to renal elimination of free compound. No evidence was obtained that 5‐FC is deaminated to 5‐fluorouracil following administration by this route. A formula is presented to calculate 5‐FC dosages in patients with renal insufficiency.

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The effects of chronic treatment with allopurinol and clofibrate on the elimination from plasma of warfarin and dicoumarol were examined in man. In addition, the binding of warfarin to human serum proteins was measured with and without clofibrate and its metabolite chlorophenoxyisobutyric acid (CPIB), both present in therapeutic concentrations. Treatment with allopurinol and clofibrate did not alter the rate of elimination of warfarin from plasma. In addition, clofibrate and CPIB caused no significant displacement of warfarin from serum proteins. This evidence supports the conclusion that the clinically significant potentiation of warfarin activity by clofibrate in man is due to an interaction at the receptor site. In contrast, treatment with allopurinol resulted in significant prolongation of the plasma half-life of dicoumarol in one of three subjects. These data are consistent with inhibition of the metabolism of dicoumarol by allopurinol in some individuals.

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