title: Protein binding and its potential for eliciting minimal systemic side effects with a novel inhaled corticosteroid, ciclesonide.
abstract: Freely circulating, protein unbound, active inhaled corticosteroid (ICS) can cause systemic adverse effects. Desisobutyryl-ciclesonide (des-CIC) is the active metabolite of ciclesonide, an effective, novel ICS for persistent asthma. This study examines the free fraction of ciclesonide and des-CIC and determines whether the presence of other agents or disease states affects protein binding. Protein binding of des-CIC (0.5, 5.0, 25, 100, and 500 ng/mL) was determined, using both equilibrium dialysis and ultrafiltration, in plasma from humans (healthy and either renally or hepatically impaired) and several animal species and in the presence of either salicylates or warfarin. Dialyzed samples were analyzed by liquid chromatography with tandem mass spectroscopy to determine both free and bound concentrations of des-CIC. After ultrafiltration, spiked plasma plus H-des-CIC was separated into free and bound fractions by centrifugation and quantified by scintillation counting. Additionally, in another study, protein binding of ciclesonide was determined by equilibrium dialysis. For equilibrium dialysis, the mean percentages of des-CIC (0.5-500 ng/mL) plasma protein binding across species were high, approximately 99%, and no apparent saturation of protein binding was observed. Results were similar for ultrafiltration analysis. Protein binding of des-CIC did not change in the presence of warfarin or salicylates or in the plasma of renally or hepatically impaired patients. The protein binding of ciclesonide was 99.4% in human serum. The very low fraction of unbound des-CIC in the systemic circulation suggests minimal systemic exposure of unbound des-CIC, thus suggesting a low potential for systemic adverse effects after administration of inhaled ciclesonide.
authors.affiliation: Sanofi-Aventis, Bridgewater, New Jersey; 2ALTANA Pharma AG, Konstanz, Germany. srohatagi@sankyopharma.com
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Luo
authors.forename: Liduo
authors.initials: L
authors.lastname: Shen
authors.forename: Zuyu
authors.initials: Z
authors.lastname: Guo
authors.forename: Christina
authors.initials: C
authors.lastname: Schemm
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Huang
authors.forename: Kelly
authors.initials: K
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: David
authors.forename: Ruediger
authors.initials: R
authors.lastname: Nave
authors.forename: S Peter
authors.initials: SP
authors.lastname: King
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D017093:Liver Failure / Q000378:metabolism; D008297:Male; D011282:Pregnenediones / Q000097:blood* / Q000493:pharmacokinetics*; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000378:metabolism; D020156:Salicylic Acid / Q000494:pharmacology; D013045:Species Specificity; D014462:Ultrafiltration; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D001798:Blood Proteins; D011282:Pregnenediones; D014859:Warfarin; C494355:desisobutyrylciclesonide; D020156:Salicylic Acid; C120481:ciclesonide