Barbiturates and Biliary Function

Abstract

This paper reviews the principal effects of phenobarbital on biliary function. Phenobarbital administration is followed by an increase in bile flow. This is mainly due to an increase in the bile salt-independent fraction of canalicular bile flow possibly through an increase in canalicular Na⁺-K⁺ ATPase activity. In addition, bile salt excretion may be increased. This effect of barbiturates on choleresis appears to be independent of microsomal enzyme induction. Barbiturates increase the uptake, storage and excretion of various dyes, for example sulfobromophthalein. Phenobarbital increases bilirubin clearance by the liver; it enhances bilirubin-UDP-glucuronyl transferase activity; whether the influence on bilirubin clearance is related to the effect on the enzyme is unknown. The influence of phenobarbital on biliary lipids is markedly different from one species to the other. In the rhesus monkey and in the rat, the relative concentration of cholesterol is decreased; in the hamster it is increased, and in man it appears largely unaffected. These effects of phenobarbital have been utilized in the treatment of chronic unconjugated hyperbilirubinemia and of certain cholestatic syndromes. Phenobarbital alone has not been useful, so far, in the treatment of cholesterol gallstones.

Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity

“…30). Administration of PB to patients with cholestatic diseases enhances bile flow and reduces pruritus (32)(33)(34). In the present study, CAR activators decreased the serum bile acid and bilirubin levels, presumably due to the up-regulation of CAR target genes expressed in liver encoding bile acid and bilirubin metabolism enzymes (cyp2b, cyp3a11, ugt1a, and gst␣), bile acid and bilirubin efflux transporters (mrp2, mrp3, and mdr1a), and suppression of the hepatic bile acid influx transporters (such as ntcp).…”

Interactions between Hepatic Mrp4 and Sult2a as Revealed by the Constitutive Androstane Receptor and Mrp4 Knockout Mice

“…We also determined if Spgp/Bsep expression changes, because PB-like inducers are known to enhance bile acid-dependent biliary excretion (36). Mrp4 protein was induced by both PB and TCPOBOP, with a greater induction in females (Fig.…”

Effects of Phenobarbitone on the Distribution, Metabolism and Biliary Excretion of Erythromycin in Rats

“…The repeated administration of PB exerts a complex influence on liver function [1], In the rat, together with liver mass and choleresis, the liver blood flow is also increased [14]; however, none of these effects can account for the increased ery thromycin concentration in the bile of PB-treated animals.…”

“…These effects were accompanied by augmented liver mass and bile flow. The possibility is discussed that erythromycin con centrates in the bile through a specialized hepatic drug transport system, activated by pheno barbitone.The elimination rate of the macrolide antibiotic erythromycin in mainly dependent on liver function [17].Experiments carried out in the animal have shown erythromycin to be metabolized in the liver via microsomal N-demethylation of the desosamine sugar moiety leading to the formation of metabolites with little or no antibiotic activity [11,13], Moreover, the un metabolized erythromycin is concentrated in the bile by which large amounts of the drug are excreted in the microbiologically active form [7,8].Phenobarbitone (PB) is a potent inducer of the hepatic microsomal drug metabolism, also capable of increasing the biliary excre tion rate of a variety of foreign chemical compounds [1,5].The possibility exists that PB may in crease the hepatic removal of erythromycin through a more active drug metabolism, a quicker biliary excretion of the drug, or pos sibly the two mechanisms together.In order to verify this hypothesis, the ef fects of PB on tissue distribution, metabo lism and biliary excretion of erythromycin were studied in the rat. …”