Disposition kinetics of diclofenac in the dual perfused rat liver.
This study investigates the hepatic disposition of diclofenac as a function of route of input: portal vein (PV) versus hepatic artery (HA) in the presence of its binding protein, albumin. The in situ dual perfused rat liver was performed using Krebs bicarbonate buffer containing human serum albumin (HSA, 0.25%-1%) at constant PV (12 mL/min) and HA (3 mL/min) flow rates. Bolus doses of [(14) C]-diclofenac and (125) I-labeled HSA were injected randomly into the HA or PV and then, after an appropriate interval, into the alternate vessel. Regardless of route of input and perfusion medium protein concentration, the hepatic outflow profile of diclofenac displayed a characteristic sharp peak followed by a slower eluting tail, indicating that its radial distribution is not instantaneous. Based on the estimated effective permeability-surface area product/blood flow ratio, hepatic uptake of diclofenac is governed by both perfusion and permeability. Fractional effluent recovery (F) increased as unbound diclofenac fraction in the perfusate decreased. Although no significant difference in hepatic clearance of diclofenac as a function of route of delivery at 0.5% and 1% HSA, it was demonstrable at 0.25% HSA (p < 0.001), when the extraction ratio is higher.
['Sahin|Selma|S|', 'Rowland|Malcolm|M|']
D000818:Animals D000894:Anti-Inflammatory Agents, Non-Steroidal D004008:Diclofenac D006801:Humans D007261:Infusions, Intra-Arterial D007262:Infusions, Intravenous D008099:Liver D008297:Male D010477:Perfusion D010539:Permeability D011485:Protein Binding D051381:Rats D017207:Rats, Sprague-Dawley D012709:Serum Albumin
disposition diclofenac portal vein hepatic artery albumin hepatic clearance biopharmaceutics classification system (BCS) dual liver perfusion pharmacokinetics protein binding