The metabolic fate of¹⁴C-ximoprofen in rats, baboons and humans

Abstract

1. The metabolic fate of 14C-ximoprofen was compared in rat (2 mg/kg), baboon (2 mg/kg) and human (approx. 0.4 mg/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 greater than keto-analogue greater than 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.

Pharmacokinetics and Metabolism of the Prodrug DB289 (2,5-Bis[4-(N-methoxyamidino)phenyl]furan Monomaleate) in Rat and Monkey and Its Conversion to the Antiprotozoal/Antifungal Drug DB75 (2,5-Bis(4-guanylphenyl)furan Dihydrochloride)

“…Pentamidine is metabolized in vitro mainly by multiple phase I cytochrome P450-induced side-chain C-hydroxylation reactions, but its minor biotransformation pathways involve N-hydroxylation to the oximes (Berger et al, 1990a(Berger et al, ,b, 1991(Berger et al, , 1992Clement and Jung, 1994). On the other hand, oximes may be hydrolyzed in vivo to the corresponding ketone (e.g., Mayo et al, 1990). Perhaps surprisingly, therefore, but in accord with the above in vitro studies, no C-oxidized metabolites of DB289 (e.g., those possessing a hydroxylated aromatic ring) were identified in the present study, although they may nevertheless have been present as minor biotransformation products.…”

Pharmacokinetics of the anti‐inflammatory drug ximoprofen in healthy young and elderly subjects: comparison with elderly rheumatic patients.

“…The latter seems more probable and might be related to lower creatinine clearances: ximoprofen and its metabolites are excreted almost entirely via the kidneys and up to about 20% dose of the former is renally excreted unchanged Mayo et al, 1990).…”

“…Ximoprofen and these two metabolites are conjugated with glucuronic acid to form ester glucuronides. The conjugated and unconjugated compounds are excreted in the urine, accounting for about 70% dose (Mayo et al, 1990). Ximoprofen is wellabsorbed and its systemic availability exceeds 90%.…”