Impact of chlorpromazine self-association on its apparent binding constants with cyclodextrins: Effect of SBE(7)-beta-CD on the disposition of chlorpromazine in the rat.
Chlorpromazine is an antipsychotic agent with poor aqueous solubility. Complexation with SBE(7)-beta-CD can aid intravenous delivery through increasing the apparent solubility of chlorpromazine. However, chlorpromazine has also been known to self-associate. This self-association can influence its capacity to interact with other chemical species, such as cyclodextrins. This study aimed to characterise the self-association and cyclodextrin binding properties of chlorpromazine, and the effect on pharmacokinetic parameters in rats when dosed with a SBE(7)-beta-CD containing formulation. Pharmacokinetic studies of chlorpromazine in the presence and absence of SBE(7)-beta-CD were undertaken in rats. The binding constant of SBE(7)-beta-CD and chlorpromazine was studied relative to chlorpromazine concentration via fluorescence. The self-association of chlorpromazine was studied by fluorescence and UV-visible spectrophotometry. Urinary excretion of intact chlorpromazine increased in the presence of SBE(7)-beta-CD. The SBE(7)-beta-CD binding constant of chlorpromazine is highly concentration dependent and the variation can be attributed to the self-association of chlorpromazine. The apparent binding constant of chlorpromazine is highest at pharmacologically relevant concentrations, providing an explanation for the significant increase in renal chlorpromazine excretion observed in rats.
McIntosh
Michelle P
MP
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia. michelle.mcintosh@pharm.monash.edu.au
Leong
Nathania
N
Katneni
Kasiram
K
Morizzi
Julia
J
Shackleford
David M
DM
Prankerd
Richard J
RJ
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D002746:Chlorpromazine / Q000737:chemistry* / Q000493:pharmacokinetics*; D003505:Cyclodextrins / Q000737:chemistry*; D008297:Male; D008823:Micelles; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D003505:Cyclodextrins; D008823:Micelles; D002746:Chlorpromazine