Abstract

The pharmacokinetics and metabolism of ³H-chlorpheniramine maleate have been studied in man. After a p.o. dose (12 mg), ³H appeared rapidly in plasma and at two hours was equivalent to 32.48 mµg of chlorpheniramine per ml; radioactivity persisted in plasma through 48 hours. At five minutes after an i.v. dose (4 mg), ³H in plasma was equivalent to 20.88 mµg of drug per ml and ³H again persisted in plasma. This persistence of plasma ³H was most probably due to tissue deposition of ³H-drug (or metabolites), directly indicated by its large volume of distribution, 250% of body weight. The drug was 72% bound to plasma protein. Unchanged drug as well as its metabolites were present in plasma, however, and in contrast to the persistent levels of ³H in plasma, the levels of ³H-chlorpheniramine declined steadily, although slowly, after the i.v. dose and after the two-hour peak after administration p.o. The plasma half-life of a p.o. dose was 12 to 15 hours and that of an i.v. dose, 28 hours. Excretion of the ³H-drug was slow and only one-third of a p.o. or i.v. dose was recovered from the excreta during 48 hours after administration. The p.o. dose was completely absorbed, however, and only small amounts of the ³H-drug were excreted into feces after its administration. Fecal excretion of ³H of an i.v. dose indicated that ³H-chlorpheniramine underwent an enterohepatic circulation. Chlorpheniramine was extensively metabolized and excreted in the urine as mono- and didesmethyl chlorpheniramine, two unidentified metabolites and small amounts of chlorpheniramine. The greatest portion of the drug was excreted as an unidentified polar metabolite(s).