title: Development of potential orphan drug therapy of intravesical liposomal tacrolimus for hemorrhagic cystitis due to increased local drug exposure.
abstract: OBJECTIVE
  The potent immunosuppressive effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis.
  
  
  METHODS
  A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected intraperitoneally in other rat groups. The tacrolimus dose was constant in all formulations at 200 μg/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II.
  
  
  RESULTS
  The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC(0-24) after intravesical administration was significantly higher than in the intraperitoneal group (p <0.05). Bladder tacrolimus AUC(0-24) did not differ significantly between the groups.
  
  
  CONCLUSIONS
  Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus may be a promising approach as an orphan drug indication for hemorrhagic cystitis.
authors.affiliation: Department of Urology, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA.
authors.forename: Jayabalan
authors.initials: J
authors.lastname: Nirmal
authors.forename: Pradeep
authors.initials: P
authors.lastname: Tyagi
authors.forename: Michael B
authors.initials: MB
authors.lastname: Chancellor
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kaufman
authors.forename: Michele
authors.initials: M
authors.lastname: Anthony
authors.forename: David D
authors.initials: DD
authors.lastname: Chancellor
authors.forename: Yen-Ta
authors.initials: YT
authors.lastname: Chen
authors.forename: Yao-Chi
authors.initials: YC
authors.lastname: Chuang
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D003556:Cystitis / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy*; D006470:Hemorrhage / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008081:Liposomes; D009965:Orphan Drug Production; D051381:Rats; D016559:Tacrolimus / Q000008:administration & dosage*
chemical_list: D007166:Immunosuppressive Agents; D008081:Liposomes; D016559:Tacrolimus