Comparative pharmacokinetic studies of tixocortol pivalate and cortisol in the rat

Comparative pharmacokinetic studies of [14C]tixocortol pivalate ([14C]TP) and [14C]cortisol were carried out in rats. A 2.5 mg/kg i.v. dose (TP and cortisol) and oral doses of 1 and 25 mg/kg (cortisol), 25-250 and 1500 mg/kg (TP) were given separately to male and female rats. 14C-Radioactivity, [14C]cortisol, [14C]TP and [14C]T were determined in plasma samples, using TLC determinations and HPLC analysis. The results showed that plasma clearance and volume of distribution values of TP were respectively 6 and 10 times larger than those of cortisol (ClC = 4.7 l/h/kg and ClTP = 33.3 l/h/kg; VdC = 1.9 l/kg and VdTP = 21.7 l/kg). TP was rapidly converted into T whose plasma concentrations were close to those of TP. By the oral route, the bioavailability of cortisol was complete, whereas that of TP and T was 0.10-0.20. For the same 25 mg/kg p.o. dose, plasma Cmax values of TP and T were 100 times less than those of cortisol. It is concluded that a faster rate of metabolism combined with a larger volume of distribution and a low oral bioavailability all contribute to the lack of systemic activity of TP compared with cortisol.