Bile pigment pharmacokinetics and absorption in the rat: therapeutic potential for enteral administration

Abstract

BACKGROUND AND PURPOSEBilirubin and biliverdin possess antioxidant and anti-inflammatory properties and their exogenous administration protects against the effects of inflammation and trauma in experimental models. Despite the therapeutic potential of bile pigments, little is known about their in vivo parenteral or enteral absorption after exogenous administration. This study investigated the absorption and pharmacokinetics of bile pigments after i.v., i.p. and intraduodenal (i.d.) administration in addition to their metabolism and routes of excretion. EXPERIMENTAL APPROACHAnaesthetized Wistar rats had their bile duct, jugular and portal veins cannulated. Bile pigments were infused and their circulating concentrations/biliary excretion were measured over 180 min. KEY RESULTSAfter i.v. administration of unconjugated bilirubin, biliverdin and bilirubin ditaurate, their plasma concentrations decreased exponentially over time. Subsequently, native and metabolized compounds appeared in the bile. When administered i.p., their absolute bioavailabilities equalled 14.0, 16.1 and 33.1%, respectively, and correspondingly 38, 28 and 34% of the same bile pigment doses were excreted in the bile. Administration of unconjugated bilirubin and bilirubin ditaurate i.d. increased their portal and systemic concentrations and their systemic bioavailability equalled 1.0 and 2.0%, respectively. Correspondingly, 2.7 and 4.6%, of the doses were excreted in the bile. Biliverdin was rapidly metabolized and these products were absorbed and excreted via the urine and bile. CONCLUSIONS AND IMPLICATIONSBile pigment absorption from the peritoneal and duodenal cavities demonstrate new routes of administration for the treatment of inflammatory and traumatic pathology. Oral biliverdin administration may lead to the production of active metabolite that protect from inflammation/complement activation.

Circulating bilirubin and defense against kidney disease and cardiovascular mortality: mechanisms contributing to protection in clinical investigations

“…Multiple mechanisms likely explain the protective effect of bilirubin (Fig. 3), including antioxidant and anti-inflammatory effects, suggesting that it could represent a biomarker and potential therapeutic target to reduce CKD/CVD risk (19). Indeed, recent studies have identified numerous molecules that either induce HO activity or partially inhibit UGT1A1, which could be used therapeutically to induce the protective effects of bilirubin in individuals at increased risk of CVD/CKD (81,105,184,199).…”

Hyperbilirubinemia modulates myocardial function, aortic ejection, and ischemic stress resistance in the Gunn rat

“…Further work is warranted to elucidate the molecular mechanisms underlying bilirubin's effects on stress resistance, contraction, vascular ejection mechanics, and determinants of afterload. Such information not only advances our understanding of the basis of protection from cardiovascular disease in GS but assists in developing novel means of manipulating myocardial function and I/R resistance (8).…”

“…All samples were centrifuged (22,000 g, 5 min), and serum aliquots were transferred into Eppendorf tubes and frozen at Ϫ80°C. Serum UCB was assessed, which involved the addition of 160 l HPLC mobile phase (0.1 M n-dioctylamine acetate in 95:5 methanol-H 2O) to 40 l serum, which precipitated serum proteins and extracted bilirubin from the sample (8). This solution was vortexed for 20 s and then centrifuged at 22,000 g for 5 min.…”

Bilirubin scavenges chloramines and inhibits myeloperoxidase-induced protein/lipid oxidation in physiologically relevant hyperbilirubinemic serum

“…These data provide a biologically relevant mechanism which could potentially contribute to reducing the incidence of CVD in GS. If this hypothesis is confirmed, strategies aimed at modifying haem catabolism and bilirubin metabolism, leading to mildly elevated circulating bilirubin, may provide a new target for therapy in humans at risk of atherosclerosis [66]. …”