Parenteral delivery of HPßCD: effects on drug-HSA binding.

ABSTRACT

It is thought that cyclodextrins, such as 2-hydroxypropyl-ß-cyclodextrin (HPßCD), will at high concentration affect pharmacokinetics of drugs through competitive binding with plasma proteins. Albumin is the major component of plasma proteins responsible for plasma protein binding. The purpose of this study was to evaluate in vitro the competitive binding of drugs between human serum albumin (HSA) and HPßCD in isotonic pH 7.4 phosphate buffer saline solution (PBS) at ambient temperature. Eight model drugs were selected based on their physicochemical properties and ability to form complexes with HSA and HPßCD. The drug/HPßCD stability constants (K(11)) were determined by the phase-solubility method and HSA/HPßCD competitive binding determined by an equilibrium dialysis method. Protein binding of drugs that are both strongly protein bound and have high affinity to HPßCD (i.e., have high K(11) value) is most likely to be affected by parenterally administered HPßCD. However, this in vitro study indicates that even for those drugs single parenteral dose of HPßCD has to be as high as 70 g to have detectable effect on their protein binding. Weakly protein bound drugs and drugs with low affinity towards HPßCD are insensitive to the cyclodextrin presence regardless their lipophilic properties.