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-ß-cyclodextrin (HPßCD) and sulfobutylether ß-cyclodextrin (SBEßCD), are found in marketed parenteral drug formulations. Depending upon the relative affinities of a coadministered medication for cyclodextrin and plasma proteins, complexation with HPßCD or SBEßCD may alter its pharmacokinetics (PK). To explore this possibility, we applied a previously developed model for competitive binding of drugs with HPßCD 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 HPßCD complexation with their therapeutic action (e.g., antibiotics), supplemented by a composite listing of concurrent medications. Stability constant (K1:1) values for drug-HPßCD 1:1 inclusion complexes were extracted from our own data and the literature. The K1:1 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 K1:1 value for HPßCD complexation to affect plasma protein binding to a degree that would be expected to alter their PK substantively, for example, to require increased doses.