The effect of parenterally administered cyclodextrins on the pharmacokinetics of coadministered drugs

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.