Absorption and disposition including enterohepatic circulation of (C-14) roquinimex after oral administration to healthy volunteers

The absorption and disposition of roquinimex (Linomide(R)) were studied in four male and two female healthy volunteers. The subjects received a single oral aqueous solution of C-14-labelled roquinimex, about 0.1 mg/kg, after an overnight fast. Blood samples were taken and urine and faeces were colle cted for 10 days after dosing. The plasma, urine and faeces concentrations of roquinimex and metabolites were determined by high-performance liquid ch romatography (HPLC) with radiochemical detection. The metabolites were iden tified by HPLC-mass spectroscopy (MS). The plasma concentration-time profil es of roquinimex exhibited a rapid absorption followed by a bi-exponential disposition. A secondary peak was observed between 6 and 8 h, indicating en terohepatic circulation (EHC) of roquinimex. The terminal disposition half- life was estimated as 27 h. The primary metabolic pathways of roquinimex we re hydroxylation, demethylation and conjugation. The major compound in plas ma was roquinimex;metabolites were only occasionally detected. In urine and faeces, roquinimex accounted for 2% of the dose and conjugated and hydroxy lated metabolites each accounted for about 30% of the dose. A model was der ived for the plasma concentrations of roquinimex and the amount of urinary excreted roquinimex to take into account EHC. This model improved the goodn ess-of-fit according to common goodness-of-fit criteria. The values of the pharmacokinetic parameters were similar using compartmental and non-compart mental methods, indicating that the contribution of EHC of roquinimex is of minor importance in the evaluation of the pharmacokinetics of roquinimex. Copyright (C) 2000 John Wiley & Sons, Ltd.