Dissolution rate-limited absorption and complete bioavailability of roquinimex in man

In order to investigate the bioavailability and the rate-limiting step of the absorption of roquinimex, an oral solution and a tablet formulation (Linomide(R)) were given to healthy volunteers. The study was conducted as a randomized three-period crossover study in seven male and seven female healthy volunteers. The subjects received an intravenous infusion, an oral solution and an oral tablet formulation, each of 5 mg (about 0.07 mg kg(-1)), as single doses after an overnight fast on three occasions, with a wash-out period of 3 weeks in between. Venous blood samples were taken over 7 days and the plasma concentrations of roquinimex were determined by high-performance liquid chromatography (HPLC) with ultraviolet (UV)-detection. The pharmacokinetics of roquinimex was characterized by a low plasma clearance, 4.9 mL h(-1) kg(-1) and a small volume of distribution, 0.22 L kg(-1). The oral bioavailability of the drug was complete for both the solution and the tablet formulation. The absorption rate was faster for the solution than for the tablet. The disposition of roquinimex was biphasic, with a terminal disposition half-life of 32 h. Between 4 and 8 hours after dosing, a secondary plasma peak was observed, indicating enterohepatic circulation of the drug. No major sex differences were shown in the pharmacokinetics of roquinimex. In conclusion, dissolution rate-limited absorption of roquinimex was shown, which demonstrates that disintegration and dissolution of the tablet play a major role in the absorption process of roquinimex. Despite the delayed absorption after administration of the tablet, the extent of absorption was complete.