No abstract

In order to investigate the bioavailability and the rate‐limiting step of the absorption of roquinimex, an oral solution and a tablet formulation (Linomide®) 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. Copyright © 1999 John Wiley & Sons, Ltd.

No abstract

A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulfonyl) ethyl]-1-nitrosourea (TCNU) tauromustine, has been investigated in a broad anti-tumour screen and, in depth toxicology and initial pharmacokinetics carried out. TCNU and its two metabolites were found to exhibit equal or better oral efficacy than that of BCNU, CCNU, MeCCNU or chorozotocin against L1210 leukemia, Walker mammary carcinoma, Lewis Lung, Harding Passey melanoma and colon carcinoma C26. The toxicological profile of TCNU after acute and 3 months treatment was similar in mice and rats to that of CCNU, with the exception that, TCNU did not cause the chronic liver disturbances found for CCNU. In dogs treated for 6 weeks with TCNU leucopenia and thrombocytopenia were the major side effects. Parent TCNU was found in all dogs. The absorption was fast, the maximum level being reach after 25 mins and the mean absorption time was 22 mins. The mean half life was 16.1 mins after intravenous and 17.4 after oral administration. The combination of these factors make TCNU an interesting clinical candidate.

Linomide, an anti-angiogenic drug, inhibits escape from "castration inhibition".