title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Michelle P
authors.initials: MP
authors.lastname: McIntosh
authors.forename: Nathania
authors.initials: N
authors.lastname: Leong
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Prankerd
mesh_terms: 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
chemical_list: D014150:Antipsychotic Agents; D003505:Cyclodextrins; D008823:Micelles; D002746:Chlorpromazine