Biodistribution processes as underestimated confounders in translational stroke research.
Pharmacological therapies in ischemic stroke have made limited progress in recent years. After many negative neuroprotection trials in humans, considerable concerns have been raised about future research strategies. This led to expert rounds, the so-called STAIR conferences, which critically reviewed previous studies and provided research recommendations. Hopes were raised that STAIR might lead to breakthroughs in neuroprotection strategies in the near future. Whether this will indeed become true, remains to be awaited. An important aspect in the context of brain pharmacotherapies is the blood-brain barrier, which prevents drugs from brain entrance. The blood-brain barrier not only acts as passive diffusion barrier, it expresses active transporters that eliminate drugs from the brain and thereby profoundly influence drug tissue levels. These transporters exhibit strong variabilities between animals and humans, which make it hardly possible to predict brain concentrations of drugs over species barriers. As such, drug biodistribution turns out to be a major confounder in pharmacological therapies. This paper claims that more precise brain accumulation studies are needed in preparation for clinical trials both in animals and in humans. This might lead to better dose selections and higher success rates of future pharmacological trials.
Hermann
Dirk M
DM
Department of Neurology, University Hospital Zurich, Frauenklinikstr. 26, CH-8091 Zurich, Switzerland. dirk.hermann@usz.ch
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D001812:Blood-Brain Barrier; D015986:Confounding Factors, Epidemiologic; D006801:Humans; D018696:Neuroprotective Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; D018696:Neuroprotective Agents