title: The effect of parenterally administered cyclodextrins on the pharmacokinetics of coadministered drugs.
abstract: Cyclodextrins are used increasingly to formulate otherwise poorly soluble molecules for clinical use. Cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether β-cyclodextrin (SBEβCD), are found in marketed parenteral drug formulations. Depending upon the relative affinities of a coadministered medication for cyclodextrin and plasma proteins, complexation with HPβCD or SBEβCD may alter its pharmacokinetics (PK). To explore this possibility, we applied a previously developed model for competitive binding of drugs with HPβCD and human serum albumin to a variety of commonly administered medications. We modeled this potential interaction in medications chosen on the basis of a hypothetical detrimental effect of HPβCD complexation with their therapeutic action (e.g., antibiotics), supplemented by a composite listing of concurrent medications. Stability constant (K(1:1)) values for drug-HPβCD 1:1 inclusion complexes were extracted from our own data and the literature. The K(1:1) values for the drugs tested ranged from 2 to 40,000 M(-1) and the plasma protein binding from about 20% to over 99%. None of the 63 drugs examined in the present study had a sufficiently high K(1:1) value for HPβCD complexation to affect plasma protein binding to a degree that would be expected to alter their PK substantively, for example, to require increased doses.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik IS-107, Iceland.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kurkov
authors.forename: Donna E
authors.initials: DE
authors.lastname: Madden
authors.forename: Daniel
authors.initials: D
authors.lastname: Carr
authors.forename: Thorsteinn
authors.initials: T
authors.lastname: Loftsson
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D061605:Administration, Intravenous; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism*; D010599:Pharmacokinetics; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000097:blood / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations; D012709:Serum Albumin; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C093196:SBE4-beta-cyclodextrin