title: L-Carnitine ester of prednisolone: pharmacokinetic and pharmacodynamic evaluation of a type I prodrug.
abstract: OBJECTIVE
  To evaluate whether PDSC, an L-carnitine ester derivative of prednisolone and OCTN2 substrate, could provide a targeted delivery of the corticosteroid into the lung tissues of an asthmatic guinea pig model.
  
  
  METHODS
  PRED (prednisolone) and PDC (an L-carnitine prodrug of prednisolone not recognized by OCTN2) served as controls. Water solubility and logP values were determined, and PDSC and PDC in vivo were quantified by LC-MS/MS.
  
  
  RESULTS
  Unlike PRED, the intra-tracheal instillation of PDSC resulted in effective and prolonged accumulation of prednisolone in the lung tissues, leading to 3.8-fold higher reduction in inflammatory cell count in the bronchoalveolar fluid, and less severe lung and bronchial lesions in the asthmatic guinea pig. PDC showed similar pharmacokinetic profile to PRED, but exhibited higher efficiency (1.7-fold higher) at reducing the inflammatory cell count and the severity of lung histopathology, possibly due to the release of L-carnitine in vivo.
  
  
  CONCLUSIONS
  The collective data suggest that PDSC has the potential to be an effective prodrug for the treatment of asthma with concomitant reduction in systemic side effects, and that novel prodrugs produced by L-carnitine conjugation can have useful applications in the targeted accumulation of drugs in the lungs.
authors.affiliation: Pharmacy, School of Medicine and Pharmacology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.
authors.forename: Jingxin
authors.initials: J
authors.lastname: Mo
authors.affiliation: Pharmacy, School of Medicine and Pharmacology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia. Electronic address: lee.lim@uwa.edu.au.
authors.forename: Lee Yong
authors.initials: LY
authors.lastname: Lim
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, PR China. Electronic address: zrzzl@vip.sina.com.
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002331:Carnitine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004951:Esterification; D005260:Female; D006168:Guinea Pigs; D006207:Half-Life; D007327:Insufflation; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008657:Metabolic Clearance Rate; D011239:Prednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011897:Random Allocation; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D011355:Prodrugs; C000599888:prednisolone succinate-carnitine; D011239:Prednisolone; D002331:Carnitine
keywords: Asthma; Pharmacokinetics–pharmacodynamics; Prednisolone; Prodrug; l-Carnitine