Impact of Chlorpromazine Self-Association on Its Apparent Binding Constants With Cyclodextrins: Effect of SBE7-β-CD on the Disposition of Chlorpromazine in the Rat

Chlorpromazine is an antipsychotic agent with poor aqueous solubility. Complexation with SBE7-β-CD can aid intravenous delivery through increasing the apparent solubility of chlorpromazine. However, chlorpromazine has also been known to self-associate. This selfassociation 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 SBE7-β-CD containing formulation. Pharmacokinetic studies of chlorpromazine in the presence and absence of SBE7-β-CD were undertaken in rats. The binding constant of SBE7-β-CD and chlorpromazine was studied relative to chlorpromazine concentration via fluorescence. The selfassociation of chlorpromazine was studied by fluorescence and UV-visible spectrophotometry. Urinary excretion of intact chlorpromazine increased in the presence of SBE7-β-CD. The SBE7- β-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.