title: Physicochemical and preclinical pharmacokinetic and toxicological evaluation of LK-423--a new phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity.
abstract: BACKGROUND
  LK-423 is a new phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity. As optimized delivery to the site of action appears crucial for further preclinical development of LK-423, the aim of this study was to perform a physicochemical and preclinical pharmacokinetic and toxicological evaluation.
  
  
  METHODS
  The solubility, partition coefficient, permeability, and stability profile were determined. Pharmacokinetics were evaluated in rats following intravenous and oral application of LK-423, and in dogs after intravenous administration and oral administration of microcapsules, designed for colon-specific delivery of LK-423 based on pH-, time-, and enzyme-controlled release mechanisms. Additionally, the acute and subchronic toxicity was examined.
  
  
  CONCLUSIONS
  LK-423 is hydrophilic, sparingly to slightly soluble, and poorly permeable. Stability profile in aqueous solution is pH dependent. A pharmacokinetic study following intravenous application to rats and dogs revealed that LK-423 is rapidly eliminated with a short terminal phase half-life, and high plasma clearance, as well as a limited distribution to the peripheral tissue. Oral bioavailability of LK-423 is low, presumably due to low permeability. Debris of insoluble microcapsule coating in feces and obtained plasma concentration profiles confirm that LK-423 microcapsules are a promising approach for local treatment of inflammatory diseases of the large intestine. Acute and a subchronic toxicity results indicate that LK-423 is a safe and nontoxic drug under the applied experimental conditions.
authors.affiliation: Lek Pharmaceuticals, Ljubljana, Slovenia.
authors.forename: Polona
authors.initials: P
authors.lastname: Smrdel
authors.forename: Iztok
authors.initials: I
authors.lastname: Grabnar
authors.forename: Igor
authors.initials: I
authors.lastname: Locatelli
authors.forename: Manica
authors.initials: M
authors.lastname: Cerne
authors.forename: Samo
authors.initials: S
authors.lastname: Andrensek
authors.forename: Natasa
authors.initials: N
authors.lastname: Kovacic
authors.forename: Albin
authors.initials: A
authors.lastname: Kristl
authors.forename: Marija
authors.initials: M
authors.lastname: Bogataj
authors.forename: Uros
authors.initials: U
authors.lastname: Urleb
authors.forename: Ales
authors.initials: A
authors.lastname: Mrhar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004151:Dipeptides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity*; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007155:Immunologic Factors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010797:Phthalimides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D004151:Dipeptides; D007155:Immunologic Factors; D010797:Phthalimides; C117773:N-(2-(2-phthalimidoethoxy)acetyl)-L-alanyl-D-glutamic acid