Human metabolism of tolfenamic acid. I. Isolation, preliminary characterization and pharmacokinetics of tolfenamic acid and its metabolites

Summary

The metabolic fate and pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent, was studied after intravenous and oral administration of¹⁴C-tolfenamic acid to one healthy volunteer. The recovery in urine was 77% of the intravenous dose and 93% of the oral dose. About 11% of the doses was found in faeces after both routes of administration whereas no radioactivity was detected in expired air, saliva or red cells. In plasma 90–99% of the radioactive compounds were bound to proteins whereasin vitro protein-binding of tolfenamic acid was 99.7%. Tolfenamic acid was biotransformed into several metabolites and only less than 10% of the doses was excreted into urine as the glucuronide/sulphate conjugate of unchanged drug. Tolfenamic acid and four metabolites were separated by TLC, together they accounted for 90–100% of urine radioactivity. Two major metabolites with preliminary identification as hydroxylation products of tolfenamic acid were isolated in pure form for further structural analysis. After fast initial decline the total plasma radioactivity decreased slowly with a mean half life of 58 hours. The elimination rate of tolfenamic acid into urine was fast with a half life of 1.9 hours whereas the metabolites were eliminated more slowly. Their elimination showed three phases, a rapid initial phase up to six hours, second phase up to 48 hours with half lives ranging from 9 to 13 hours and a third terminal slow, quantitatively minor, phase thereafter.

In conclusion, tolfenamic acid is practically completely absorbed from the GI tract, probably undergoes considerable enterohepatic circulation, is highly protein bound and extensively metabolized to several metabolites slowly excreted into urine.