caa a22 4500 47712559X CHVBK 20180405111648.0 cr unu---uuuuu 170330e19970101xx s 000 0 eng 10.1023/A:1012007517877 doi (NATIONALLICENCE)springer-10.1023/A:1012007517877 Extrahepatic Ischemia-Reperfusion Injury Reduces Hepatic Oxidative Drug Metabolism as Determined by Serial Antipyrine Clearance [Elektronische Daten] [Bill Gurley, Gary Barone, Kazuto Yamashita, Sabrena Polston, Mark Estes, Antionetta Harden] Purpose. 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 TNFα) 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-I-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-1 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. Plenum Publishing Corporation, 1997 ischemia-reperfusion injury nationallicence hepatic clearance nationallicence anti-pyrine nationallicence cytokines nationallicence interleukin-6 nationallicence tumor necrosis factor nationallicence Gurley Bill Department of Pharmaceutics, University of Arkansas for Medical Sciences, College of Pharmacy, 4301 W. Markham St., Slot 522, 72205, Little Rock, Arkansas aut Barone Gary Department of Surgery, Division of Transplant Surgery, University of Arkansas for Medical Sciences, 72205, Little Rock, Arkansas aut Yamashita Kazuto Department of Veterinary Surgery 1, School of Veterinary Medicine, Rakuno Gakuen University, 069, Hokkaido, Japan aut Polston Sabrena Department of Pharmaceutics, University of Arkansas for Medical Sciences, College of Pharmacy, 4301 W. Markham St., Slot 522, 72205, Little Rock, Arkansas aut Estes Mark Department of Pharmaceutics, University of Arkansas for Medical Sciences, College of Pharmacy, 4301 W. Markham St., Slot 522, 72205, Little Rock, Arkansas aut Harden Antionetta University of Arkansas at, 72206, Little Rock, Little Rock, Arkansas aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/1(1997-01-01), 67-72 0724-8741 14:1<67 1997 14 11095 https://doi.org/10.1023/A:1012007517877 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012007517877 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gurley Bill Department of Pharmaceutics, University of Arkansas for Medical Sciences, College of Pharmacy, 4301 W. Markham St., Slot 522, 72205, Little Rock, Arkansas aut NATIONALLICENCE 700 1- Barone Gary Department of Surgery, Division of Transplant Surgery, University of Arkansas for Medical Sciences, 72205, Little Rock, Arkansas aut NATIONALLICENCE 700 1- Yamashita Kazuto Department of Veterinary Surgery 1, School of Veterinary Medicine, Rakuno Gakuen University, 069, Hokkaido, Japan aut NATIONALLICENCE 700 1- Polston Sabrena Department of Pharmaceutics, University of Arkansas for Medical Sciences, College of Pharmacy, 4301 W. Markham St., Slot 522, 72205, Little Rock, Arkansas aut NATIONALLICENCE 700 1- Estes Mark Department of Pharmaceutics, University of Arkansas for Medical Sciences, College of Pharmacy, 4301 W. Markham St., Slot 522, 72205, Little Rock, Arkansas aut NATIONALLICENCE 700 1- Harden Antionetta University of Arkansas at, 72206, Little Rock, Little Rock, Arkansas aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/1(1997-01-01), 67-72 0724-8741 14:1<67 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer