Pharmacokinetics of repinotan in healthy and brain injured animals.

Repinotan hydrochloride (repinotan) is a highly potent and selective 5-HT1A full receptor agonist. The ability of repinotan to cross the blood-brain barrier (131313) and penetrate into rat brain tissue was investigated, because rapid penetration into brain tissue is thought to be essential for neuroprotective efficacy. Intravenous (i.v.) repinotan was rapidly distributed into brain, and the distribution equilibrium between blood and brain was reached immediately after the start of infusion. Free concentrations of repinotan were identical in brain and plasma, indicating that repinotan crosses the BBB freely in both directions with diffusion as a driving force. The brain concentration of repinotan was determined by the free plasma concentration. Thus, the total plasma concentration of repinotan (sum of bound and unbound compound) is only indicative for the brain concentration as long as the unbound fraction remains constant. Metabolites of repinotan do not penetrate the BBB and are retained in the perfusing blood due to their increased polarity. The penetration of [C-14] repinotan into ischemic areas of the brain was dependent on time. In studies using injured animals (pMCAO), high levels of [C-14] repinotan could be detected in ischemic areas when the compound was administered up to 5 h post injury. [C-14] repinotan radioactivity could no longer be detected in ischemic areas when administered 18 h after pMCA-O. After the end of infusion, repinotan was rapidly and completely eliminated from rat brains. Elimination occurred in parallel from plasma and brain with half-lives of about 1 h. In conclusion, repinotan rapidly and to a considerable extent penetrates into brain tissue of healthy and injured animals. Copyright (c) 2005 John Wiley & Sons, Ltd.