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

Abstract

Background and purpose: Bilirubin 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 approach: Anaesthetized 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 RESULTS After 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 implications: Bile 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.

Figure 1

Effects of i.v. treatment with sodium bilirubinate (A, B), sodium biliverdinate (C, D) and bilirubin ditaurate (E, F) on the plasma concentration (left panels) of unconjugated bilirubin, biliverdin or bilirubin ditaurate; and rate of total bile pigment excretion (right panels; BDG, bilirubin diglucuronide; BMG, bilirubin monoglucuronide; UCB, unconjugated bilirubin; BV, biliverdin; stacked columns). Data points in in (A, C, E) indicate plasma concentrations at 0, 2, 5, 10, 15, 20, 30, 60, 90, 120, 180 min. *P < 0.05 versus t₀; #P < 0.05 treatment versus vehicle group (systemic unconjugated bilirubin concentration or rate of total bile pigment excretion) at that time point.

Figure 2

Effects of i.p. treatment with sodium bilirubinate (A, B), sodium biliverdinate (C, D) and bilirubin ditaurate (E, F) on the plasma concentration (left panels) of unconjugated bilirubin, biliverdin or bilirubin ditaurate; and rate of total bile pigment excretion (right panels; BDG, bilirubin diglucuronide; BMG, bilirubin monoglucuronide; UCB, unconjugated bilirubin; BV, biliverdin; stacked columns). Data points in (A, C, E) indicate plasma concentrations at 0, 15, 30, 60, 90, 120, 150, 180 min. *P < 0.05 versus t₀; #P < 0.05 treatment versus vehicle group (systemic unconjugated bilirubin concentration or rate of total bile pigment excretion) at that time point.

Figure 3

Effects of i.d. treatment with sodium bilirubinate (A, B), sodium biliverdinate (C, D) and bilirubin ditaurate (E, F) on the plasma concentration (left panels) of unconjugated bilirubin, biliverdin or bilirubin ditaurate and the rate of total bile pigment excretion (right panels; BDG; bilirubin diglucuronide, BMG; bilirubin monoglucuronide, UCB; unconjugated bilirubin; BV, biliverdin; stacked columns). Data points in panels (A, C, E) indicate plasma concentrations at 0, 15, 30, 60, 90, 120, 150, 180 min. *P < 0.05 versus t₀; #P < 0.05 treatment versus vehicle group (systemic unconjugated bilirubin concentration or rate of total bile pigment excretion) at that time point; ^P < 0.05 portal versus systemic concentrations in the treatment group.

Figure 4

Cumulative biliary excretion of sodium bilirubinate, sodium biliverdinate and bilirubin ditaurate after i.v. (A), i.p. (B) and i.d. (C) administration. For clarity, standard error bars on the cumulative excreted dose data after i.p. bilirubin ditaurate administration (B) have been omitted but were similar in magnitude to the other compounds.