Salicylamide is metabolized in man by biotransformation to salicylamide glucuronide, salicylamide sulfate, and gentisamide glucuronide. The metabolites are quantitatively and rapidly excreted in urine. Study of the metabolism of this drug in volunteers during episodes of pyrogen-induced fever shows a significant reduction in the half-life (t½) of the excretion of the drug metabolites. The proportion of the drug transformed to its major metabolite, salicylamide glucuronide, is significantly reduced by fever, with concomitant increase in the proportion of one or both of the other metabolites. Thus, the pattern of urinary metabolites of salicylamide is altered. The shortened t½ of the metabolite excretion is probably due to increased hepatic and renal blood flow known to accompany pyrogen-induced fever. This concept was supported by the observation that when two subjects were placed in a high-temperature environmental chamber, a condition in which hepatic and renal blood flows are known to diminish, the t½ of salicylamide metabolite excretion actually increased. No simple explanation exists to explain the changed metabolite pattern noted during febrile periods. It is most likely to be due to complex interactions between the direct or indirect effects of the pyrogens and the factors affecting the hepatic biotransformation of drugs.

Despite the widespread use of pharmacological agents such as analgesics, antipyretics, antibiotics, and antimetabolites in diseases associated with fever, little is known of the effect of fever on the disposal of drugs in man. We have studied the metabolism of salicylamide in normal volunteers before and after induction of artificial fever by administration of etiocholanolone or endotoxin. Salicylamide (o-hydroxybenzamide) is an amidederivative of salicylic acid that has mild analgesic and antipyretic properties. It is rapidly absorbed from the gastrointestinal tract after oral ingestion and undergoes biotransformation primarily to its ether glucuronide and ester sulfate. A small proportion of the drug is metabolized to gentisamide glucuronide. All metabolites are rapidly eliminated by renal excretion. The metabolites are stable in urine and their assay is relatively simple. These properties, plus the absence of significant binding of the free drug to plasma proteins, make salicylamide a convenient agent in the investigation of the effect of short-term physiologic perturbations such as artificial fever on drug metabolism.
The method used in these studies is based on a procedure developed and extensively employed by Vesell and his coworkers in which each normal volunteer serves as his own control so that the rate of decay of a test drug is determined in each individual both before and after the introduction of some form of treatment. For example, using antipyrine half-lives in the plasma of identical and fraternal twins before and after treatment for 2 wk with phenobarbital, Vesell and Page demonstrated that large differences among normal subjects in phenobarbital-induced reduction of plasma anti-' pyrine half-life were under very rigid genetic control. The method was later used to establish that the following drugs, administered in commonly employed doses for a given time, prolonged the metabolism of other therapeutic agents: nortriptyline, allopurinol, disulfiram, and L-dopa. Ethanol was shown to accelerate the metabolism of antipyrine.