TY - JOUR
T1 - Preclinical comparison of intravenous melphalan pharmacokinetics administered in formulations containing either (SBE)7m-beta-cyclodextrin or a co-solvent system
AU - Koltun, Maria
AU - Morizzi, Julia
AU - Katneni, Kasiram
AU - Charman, Susan A
AU - Shackleford, David
AU - McIntosh, Michelle Paula
PY - 2010
Y1 - 2010
N2 - The aim of this work was to evaluate the impact of sulfobutyl ether I?-cyclodextrin ((SBE)7a??m-I?-CD; CaptisolA?) on the in vivo pharmacokinetics of melphalan in rats. Melphalan is a chemically unstable antineoplastic drug which in the current commercial formulation (AlkeranA? for Injection) has some limitations with regard to solubility, stability and biocompatibility. Melphalan formulations containing (SBE)7a??m-I?-CD have previously been evaluated in vitro and shown to significantly reduce the rate of degradation and to simplify the reconstitution procedure for lyophilised melphalan. In this study, melphalan was administered intravenously in rats in formulations that either contain (SBE)7a??m-I?-CD or a co-solvent system (i.e. the commercial formulation). Pharmacokinetic parameters, including half-life, volume of distribution, clearance and extent of renal elimination of melphalan were essentially unchanged between the two formulations. These findings indicate that the pharmacokinetics of melphalan are not altered in the presence of (SBE)7a??m-I?-CD consistent with a rapid shift in the equilibrium to the fully dissociated drug from the fraction associated with the cyclodextrin host molecule upon intravenous administration.
AB - The aim of this work was to evaluate the impact of sulfobutyl ether I?-cyclodextrin ((SBE)7a??m-I?-CD; CaptisolA?) on the in vivo pharmacokinetics of melphalan in rats. Melphalan is a chemically unstable antineoplastic drug which in the current commercial formulation (AlkeranA? for Injection) has some limitations with regard to solubility, stability and biocompatibility. Melphalan formulations containing (SBE)7a??m-I?-CD have previously been evaluated in vitro and shown to significantly reduce the rate of degradation and to simplify the reconstitution procedure for lyophilised melphalan. In this study, melphalan was administered intravenously in rats in formulations that either contain (SBE)7a??m-I?-CD or a co-solvent system (i.e. the commercial formulation). Pharmacokinetic parameters, including half-life, volume of distribution, clearance and extent of renal elimination of melphalan were essentially unchanged between the two formulations. These findings indicate that the pharmacokinetics of melphalan are not altered in the presence of (SBE)7a??m-I?-CD consistent with a rapid shift in the equilibrium to the fully dissociated drug from the fraction associated with the cyclodextrin host molecule upon intravenous administration.
UR - http://onlinelibrary.wiley.com/doi/10.1002/bdd.725/abstract
U2 - 10.1002/bdd.725
DO - 10.1002/bdd.725
M3 - Article
SN - 0142-2782
VL - 31
SP - 450
EP - 454
JO - Biopharmaceutics and Drug Disposition
JF - Biopharmaceutics and Drug Disposition
IS - 8-9
ER -