title: Extrahepatic ischemia-reperfusion injury reduces hepatic oxidative drug metabolism as determined by serial antipyrine clearance.
abstract: OBJECTIVE
  All transplanted solid organs experience some degree of ischemia-reperfusion (I-R) injury. This I-R injury can contribute to graft dysfunction which stems in part from the acute phase response and a resultant host of cytokines. Recent evidence suggests that organs remote to the site of I-R injury can be affected by circulating cytokines originating from these I-R injuries. Since many of these acute phase cytokines inhibit hepatic cytochrome P-450 (CYP) enzymes, we chose to investigate whether extrahepatic I-R injuries could influence hepatic oxidative drug metabolism.
  
  
  METHODS
  Fifteen dogs were divided into three surgical groups: (I) sham I-R; (II) bilateral normothermic renal I-R; and (III) normothermic intestinal I-R. Antipyrine (AP) was selected as a model substrate and administered intravenously at a dose of 10 mg/kg. AP serum concentrations were determined by HPLC and cytokine activity (IL-1, IL-6, and TNFalpha) was measured via bioassay. Serial AP clearance and serum cytokine concentrations were determined 3 days prior to and at 4 hr, 24 hr, 3 days and 7 days after surgery. Hematology and blood chemistries were monitored throughout the study period.
  
  
  RESULTS
  AP clearance was significantly reduced in groups II and III at 4 and 24 hrs post-l-R injury, while AP binding and apparent volume of distribution were unaffected. Peak levels of TNF and IL-6 activity occurred at 1 and 4 hours, respectively. IL-I activity was not detected in any group. AP clearance correlated strongly to circulating levels of IL-6 (r = -0.789, p = 0.0002).
  
  
  CONCLUSIONS
  Our findings indicate that extrahepatic I-R injury can affect hepatic oxidative drug metabolism and this effect is mediated in part by circulating cytokines.
authors.affiliation: Department of Pharmaceutics, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Gurley
authors.forename: G W
authors.initials: GW
authors.lastname: Barone
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.forename: S
authors.initials: S
authors.lastname: Polston
authors.forename: M
authors.initials: M
authors.lastname: Estes
authors.forename: A
authors.initials: A
authors.lastname: Harden
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007422:Intestines / Q000098:blood supply; D007668:Kidney / Q000098:blood supply; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D015427:Reperfusion Injury / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000983:Antipyrine