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.
Plazzi
P V
PV
Dipartimento Farmaceutico, Università degli Studi di Parma, Italy.
Mor
M
M
Silva
C
C
Bordi
F
F
Morini
G
G
Crivori
M
M
Caretta
A
A
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D006633:Histamine Antagonists / Q000378:metabolism / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects*
D001798:Blood Proteins; D006633:Histamine Antagonists; D010743:Phospholipids; D010880:Piperidines; D018100:Receptors, Histamine H3; C052075:thioperamide