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dc.contributor.authorElliott, S Len
dc.contributor.authorMorgan, Denis Jen
dc.contributor.authorAngus, Peter Wen
dc.contributor.authorGhabrial, Hanyen
dc.contributor.authorWatson, R Gen
dc.contributor.authorSmallwood, R Aen
dc.identifier.citationBiochemical Pharmacology; 45(3): 573-8en
dc.description.abstractWe investigated, using the single-pass isolated perfused rat liver preparation, whether the centrilobular location of hepatic oxidative drug metabolism could be a contributing factor to the marked sensitivity of drug oxidation to hypoxia. Livers (N = 7) were each perfused for 130 min with 2 micrograms/mL (+)-propranolol, a drug metabolized almost entirely by oxidation in the rat. The direction of flow was reversed after 60 min, the order of flow direction being randomized. Normal oxygenation was used during the first 30 min of antegrade and of retrograde perfusion, but in the second 30 min perfusate was equilibrated with a N2/O2 mixture designed to reduce hepatic oxygen delivery by half. During normal oxygenation there was no significant difference between antegrade and retrograde perfusion in hepatic oxygen delivery and physiological parameters such as oxygen consumption and extraction, perfusion pressure and bile flow. During hypoxia, mean oxygen delivery was slightly lower with retrograde perfusion (retrograde: mean = 2.37 mumol/min/g liver, range = 1.56-3.17; antegrade: mean = 2.90 mumol/min/g liver, range = 1.96-4.08; P = 0.04), but there was no significant difference in physiological parameters within each liver (P > 0.05). Propranolol clearance during normal oxygenation was similar to the perfusion rate (10 mL/min) and was the same for both directions of perfusion (antegrade 9.88 +/- 0.07 mL/min, retrograde 9.88 +/- 0.13 mL/min, P > 0.05). Hypoxia reduced propranolol clearance substantially, but the decrease was significantly greater with antegrade perfusion (5.65 +/- 1.89 mL/min) than with retrograde perfusion (6.76 +/- 1.95 mL/min, P = 0.014). Oxidative drug metabolism is located primarily in the centrilobular zone and sinusoidal oxygen concentration is lowest in the "downstream" zone with both antegrade and retrograde perfusion. These findings suggest that the centrilobular location of propranolol metabolism may influence the effect of hypoxia on propranolol elimination, but is not a major contributor to the marked sensitivity of propranolol elimination to hypoxia antegrade perfusion.en
dc.subject.otherOxygen Consumptionen
dc.subject.otherRats, Sprague-Dawleyen
dc.titleThe effect of hypoxia on propranolol clearance during antegrade and retrograde flow in the isolated perfused rat liver preparation.en
dc.typeJournal Articleen
dc.identifier.journaltitleBiochemical pharmacologyen
dc.identifier.affiliationUniversity of Melbourne, Department of Medicine, Heidelberg Repatriation Hospital, Australiaen
dc.type.austinJournal Articleen
item.fulltextNo Fulltext-
item.openairetypeJournal Article-
item.grantfulltextnone- Liver Transplant Unit- and Hepatology-
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