title: Effects of duration of ischemia and donor pretreatment with methylprednisolone or its macromolecular prodrug on the disposition of indocyanine green in cold-preserved rat livers.
abstract: OBJECTIVE
  Cold preservation of the liver before transplantation may change uptake and excretory functions of hepatocytes. We hypothesized that an increase in the duration of preservation would result in a progressive decrease in the hepatic uptake and/or biliary excretion of indocyanine green (ICG), which would be attenuated by pharmacologic interventions.
  
  
  METHODS
  Donor rats (n = 40) were administered saline (control) or single 5 mg/kg doses of methylprednisolone (MP) or its liver-targeted prodrug (DMP) 2 h prior to liver harvest. Following preservation in cold University of Wisconsin solution for 0, 24, 48, or 72 h, livers were reperfused in a single-pass manner for 30 min in the presence of ICG (approximately 4 microg/ml), followed by 60 min of ICG-free perfusion. The inlet, outlet, and bile concentrations of ICG were measured periodically by high performance liquid chromatography (HPLC), and kinetic parameters were estimated.
  
  
  RESULTS
  Effects of duration of preservation: In unpreserved livers, a significant portion of ICG dose (16%) was effluxed from the liver during the washout period. Cold preservation for 24-72 h progressively increased (p < 0.05) the efflux of ICG (>2-fold at 72 h). Similarly, average extraction ratio showed a modest (30-40%) decrease with increasing preservation time (p < 0.05). However, biliary excretion of ICG showed the most sensitivity to the preservation time (14 to >800-fold decline). Effects of pretreatment: DMP caused significant (p < 0.05) increases in biliary ICG levels (>12-fold) and bile flow rates (6-15-fold) of preserved livers. Although MP pretreatment significantly (p < 0.05) increased (6-fold) bile flow rates in 48-h preserved livers, its effects on biliary ICG levels were not significant (p > 0.05).
  
  
  CONCLUSIONS
  Biliary excretion of ICG is the most sensitive kinetic parameter to prolonged cold ischemia-reperfusion injury in a rat liver perfusion model. The injury may be significantly attenuated by pharmacologic pretreatment of the liver donors.
authors.affiliation: School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
authors.forename: Anjaneya P
authors.initials: AP
authors.lastname: Chimalakonda
authors.forename: Reza
authors.initials: R
authors.lastname: Mehvar
mesh_terms: D000135:Acid Phosphatase / Q000737:chemistry / Q000378:metabolism; D000410:Alanine Transaminase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000737:chemistry / Q000378:metabolism; D001646:Bile / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015925:Cryopreservation; D003911:Dextrans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004338:Drug Combinations; D007208:Indocyanine Green / Q000378:metabolism* / Q000494:pharmacology; D007511:Ischemia; D007770:L-Lactate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017093:Liver Failure; D016031:Liver Transplantation / Q000379:methods; D008776:Methylprednisolone Hemisuccinate / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D009926:Organ Preservation / Q000379:methods; D019188:Organ Preservation Solutions; D010477:Perfusion / Q000379:methods; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury; D013997:Time Factors; D014019:Tissue Donors
chemical_list: D003911:Dextrans; D004338:Drug Combinations; D019188:Organ Preservation Solutions; D011355:Prodrugs; D008776:Methylprednisolone Hemisuccinate; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000135:Acid Phosphatase; D007208:Indocyanine Green