title: Effects of Pringle maneuver and partial hepatectomy on the pharmacokinetics and blood-brain barrier permeability of sodium fluorescein in rats.
abstract: Liver diseases are known to affect the function of remote organs. The aim of the present study was to investigate the effects of Pringle maneuver, which results in hepatic ischemia-reperfusion (IR) injury, and partial hepatectomy (Hx) on the pharmacokinetics and brain distribution of sodium fluorescein (FL), which is a widely used marker of blood-brain barrier (BBB) permeability. Rats were subjected to Pringle maneuver (total hepatic ischemia) for 20 min with (HxIR) or without (IR) 70% hepatectomy. Sham-operated animals underwent laparotomy only. After 15 min or 8h of reperfusion, a single 25-mg/kg dose of FL was injected intravenously and serial (0-30 min) blood and bile and terminal brain samples were collected. Total and free (ultrafiltration) plasma, total brain homogenate, and bile concentrations of FL and/or its glucuronidated metabolite (FL-Glu) were determined by HPLC. Both IR and HxIR caused significant reductions in the biliary excretions of FL and FL-Glu, resulting in significant increases in the plasma AUC of the marker. Additionally, the free fraction of FL in plasma was significantly increased by HxIR. Although the brain concentrations of FL were increased by almost twofold in both IR and HxIR animals, the brain concentrations corrected by the free FL AUC (and not the total AUC) were similar in both groups at either time points. It is concluded that Pringle maneuver and/or partial hepatectomy substantially alters the hepatobiliary disposition, plasma AUC, plasma free fraction, and brain accumulation of FL without altering the BBB permeability to the marker.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Miah
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: Imam H
authors.initials: IH
authors.lastname: Shaik
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA; Center for Blood-Brain Barrier Research, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bickel
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA; Center for Blood-Brain Barrier Research, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA; Department of Biomedical and Pharmaceutical Sciences, Chapman University, School of Pharmacy, Irvine, CA, USA. Electronic address: mehvar@chapman.edu.
authors.forename: Reza
authors.initials: R
authors.lastname: Mehvar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000418:Albumins / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D019793:Fluorescein / Q000493:pharmacokinetics*; D006498:Hepatectomy / Q000379:methods*; D019194:Ischemic Preconditioning; D008099:Liver / Q000378:metabolism; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000637:Transaminases / Q000378:metabolism
chemical_list: D000418:Albumins; D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; C503597:Slco1a4 protein, rat; C086860:glutathione transporter; D000255:Adenosine Triphosphate; D000637:Transaminases; D019793:Fluorescein
keywords: Blood–brain barrier permeability; Hepatic ischemia–reperfusion injury; Partial hepatectomy; Pharmacokinetics; Pringle maneuver; Sodium fluorescein