Parenteral delivery of HPβCD: effects on drug-HSA binding

Abstract

It is thought that cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin (HPβCD), 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 HPβCD 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 HPβCD. The drug/HPβCD stability constants (K(1:1)) were determined by the phase-solubility method and HSA/HPβCD competitive binding determined by an equilibrium dialysis method. Protein binding of drugs that are both strongly protein bound and have high affinity to HPβCD (i.e., have high K(1:1) value) is most likely to be affected by parenterally administered HPβCD. However, this in vitro study indicates that even for those drugs single parenteral dose of HPβCD 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 HPβCD are insensitive to the cyclodextrin presence regardless their lipophilic properties.

Fig. 1

Typical kinetic curve for determination of equilibration time for the protein binding studies using ketoprofen as a sample drug

Fig. 2

Relationship between the drug-HPβCD complex stability coefficient, K _CD, and drug fraction bound to HSA, . Numbering coincides with Table I

Fig. 3

Binding profiles of studied drugs to 4% w/v HSA at various concentrations of HPβCD. The error bars represent standard deviation

Fig. 4

Simulated plasma concentration (C _P)—time profile in man (70 kg) after intravenous administration of 8 g of HPβCD twice a day for 4 days. One compartment open model; V _D = 0.2 l/kg; t _1/2 = 1.7 h