title: The effect of intravenous sulfobutylether7 -β-cyclodextrin on the pharmacokinetics of a series of adamantane-containing compounds.
abstract: Intravenously administered (i.v.) drug-cyclodextrin (CD) inclusion complexes are generally expected to dissociate rapidly and completely, such that the i.v. pharmacokinetic profile of a drug is unchanged in the presence of CD. The altered pharmacokinetics of a synthetic ozonide in rats has been attributed to an unusually high-binding affinity (2.3 × 10(6) M(-1) ) between the drug and sulfobutylether7 -β-cyclodextrin (SBE7 -β-CD) with further studies suggesting a significant binding contribution from the adamantane ring. This work investigated the binding affinity of three adamantane derivatives [amantadine (AMA), memantine (MEM) and rimantadine (RIM)] to SBE7 -β-CD and the impact of complexation on their i.v. pharmacokinetics. In vitro studies defined the plasma protein binding, as well as the impact of SBE7 -β-CD on erythrocyte partitioning of each compound. SBE7 -β-CD binding constants for the compounds were within the typical range for drug-like molecules (10(2) -10(4) M(-1) ). The pharmacokinetics of AMA and MEM were unchanged; however, significant alteration of RIM plasma and urinary pharmacokinetics was observed when formulated with CD. In vitro studies suggested two factors contributing to the altered pharmacokinetics: (1) low plasma protein binding of RIM, and (2) decreased erythrocyte partitioning in the presence of high SBE7 -β-CD concentrations. This work demonstrated the potential for typical drug-cyclodextrin interactions to alter drug plasma pharmacokinetics.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, 3052, Australia.
authors.forename: Nathania J
authors.initials: NJ
authors.lastname: Leong
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Prankerd
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Mcintosh
mesh_terms: D000547:Amantadine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008954:Models, Biological; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D012299:Rimantadine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000097:blood
chemical_list: D047392:beta-Cyclodextrins; D012299:Rimantadine; C093196:SBE4-beta-cyclodextrin; D000547:Amantadine; D008559:Memantine
keywords: clearance; complexation; cyclodextrins; distribution; pharmacokinetics; renal excretion