Rat protein binding and cerebral phospholipid affinity of the H3-receptor antagonist thioperamide

The binding of thioperamide, a known H3-receptor antagonist, to rat plasma and proteins and its affinity for rat cerebral phospholipids are investigated. Thioperamide is strongly bound to plasma proteins (95-80% at plasma concentrations of 3.5-400 micrograms mL-1), and its binding can be resolved into two components a high-affinity, saturable component and a non-specific component. The drug has a high affinity for cerebral phospholipids, with a partition coefficient of approximately 100 (log K = 2.06 +/- 0.14), which should promote brain penetration and accumulation. Protein binding and cerebral phospholipid affinity can suggest the explanation of some differences reported in the literature on thioperamide distribution data: at low plasma concentrations of the drug, its protein binding (95% at 3.5 micrograms mL-1) can prevent brain accumulation, while at higher concentrations the free plasma fraction suddenly increases (> 10% at 18 micrograms mL-1) and it allows passive distribution to lipophilic tissues such as brain tissue.