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.

Subcellular distribution in vivo of testosterone and salt extractability of nuclear androgen complexes in the prostate and prostatic adenocarcinoma: effect of estrogen treatment.

The distribution of injected [3H]testosterone into nuclear (Nt) mitochondrial-microsomal (Mp) and cytosolic fractions (Cs) obtained from hormone-dependent R-3327 Dunning tumor, dorsal prostate, ventral prostate and heart ventricle, as a non-target tissue, was studied. Since it has been suggested that salt resistant steroid receptor complexes may represent acceptor sites, extractability of nuclear androgen complexes with high KCl (0.6 M) solution was also determined. Both orchiectomized (Or) and estrogen treated (E2) rats were used. The distribution of bound radioactivity between Nt and Cs fractions was very similar in tumors, dorsal and ventral prostate, being approximately 50% and 10% in Nt and Cs, respectively. In heart the corresponding figures were 15% and 12%, respectively. The concentration of radioactivity/mg protein in nuclear KCl-extract (Ne) from tumors was approximately 10-fold higher than that in the salt-resistant (Nr) fraction and also nearly 10-fold higher than that in Cs. Similar distribution patterns were observed in dorsal and in ventral prostate, but the concentration in Ne from ventral prostate was higher than that from tumors or dorsal prostate. Both total and bound radioactivity in Cs from heart was similar to that in the tumors, whereas the concentration in Ne from heart was < 2% of that in Ne from tumors. No significant differences were found in the distribution of radioactivity in tumors or tissues obtained from Or or E2 rats.(ABSTRACT TRUNCATED AT 250 WORDS)