Pharmacokinetics of intravenous and oral tolmesoxide

A high pressure liquid chromatographic assay was developed for simultaneous measurement of the plasma levels of tolmesoxide and its principal metabolite, RX71112. The assay was used to study the disposition of intravenous and oral tolmesoxide in ten normotensive subjects. Two exponential terms were required to describe the disposition of the drug following intravenous administration, whilst a single exponential term sufficed to account for the decay in the plasma concentration after oral administration. The bioavailability of oral tolmesoxide from capsules averaged 84.5% and was independent of dose. The mean half-life after i.v. dosing was 2.6 h (+/- 0.3 SEM) compared to values of 1.9 h (+/- 0.1 SEM) and 2.7 h (+/- 0.5 SEM) following 200 and 400 mg oral doses respectively. In all subjects RX71112 appeared in plasma shortly after tolmesoxide following both routes of administration. The terminal half-life of the metabolite was significantly longer than tolmesoxide with a mean value of 4.9 h (+/- 0.9 SEM) following the 200 mg oral dose of tolmesoxide. The binding of tolmesoxide and RX71112 at therapeutic plasma concentration was 36.8% (+/- 0.5 SEM) and 58.5% (+/- 0.3 SEM) and this remained unchanged at higher concentrations.