The metabolic fate of ¹⁴C-ximoprofen in rats, baboons and humans

Abstract

1. The metabolic fate of ¹⁴C-ximoprofen was compared in rat (2mg/kg), baboon (2mg/kg) and human (approx. 0-4mg/kg). An oral dose was well absorbed in all three species as indicated by urinary excretion of 80%, 86% and 94% dose respectively in 5 days: excreted in the faeces were 14%, 2% and 2% dose respectively.

2. Total ¹⁴C in plasma reached peak concentrations at 1–1.5 h in humans and earlier in animals. In humans, plasma ¹⁴C was initially associated mainly with unchanged drug which declined with a half-life of about 2 h (plasma ¹⁴C t1/2 about 8 h; cf. about 6 h in animals).

3. Tissue ¹⁴C concentrations in rats were generally similar to those in baboons at 1 h after dosing, decreasing substantially at later times. The distribution of ¹⁴C was consistent with that of a compound readily eliminated.

4. The major biotransformation products of ximoprofen were formed by hydrolysis to the keto-analogue followed by reduction to the hydroxy-analogue and conjugation of these two compounds. The same major metabolites were detected in urine of rat, baboon and humans but there was (a) complete biotransformation of ximoprofen in the rat, (b) an apparent difference in the nature of the conjugated component (s) in rat urine and those in baboon and human urine, (c) only one hydroxy-analogue detected in human urine but two such compounds in animal urine as indicated by mass spectrometry.

5. In human plasma at peak concentrations, the relative importance of circulating components was ximoprofen > keto-analogue > hydroxy-analogue, whereas in the plasma of the animal species this order was reversed, consistent with the more extensive biotransformation of ximoprofen observed in rat or baboon.