Bilirubin is an endogenous compound that can be toxic under certain conditions but, on the other hand, mild unconjugated hyperbilirubinaemia might protect against cardiovascular diseases and tumour development. Serum bilirubin levels are often enhanced under a variety of clinical conditions. These are discussed and the mechanisms are outlined.

http://www.sld.cu/galerias/pdf/sitios/gastroenterologia/bilirrubina.pdf

Bilirubin in clinical practice: a review.

The pharmacological effect of a drug is partly dependent upon its concentration at its site of action, which in turn is partly dependent upon its rate of elimination. The rate of elimination of many lipophilic drugs is governed by the activity of the hepatic microsomal mixed-function oxidases. Consequently any alteration in the activity of these enzymes may result in a modification of drug action. A wide range of chemically unrelated substances may stimulate the activity of the mixedfunction oxidases by enzyme induction. The drugs most frequently encountered as enzymeinducing agents in man are barbiturates, rifampicin and Phenytoin. Enhancement of drug metabolism by ethanol, tobacco smoking and diet may also involve enzyme induction. Enzyme induction is normally associated with a reduction in drug efficacy but may also alter the toxicity of certain substances. Enzyme induction has been assessed in man by measuring changes in the pharmacokinetics of a marker drug, or changes in the disposition of endogenous compounds such as γ-glutamyltranspeptidase, D-glucaric acid and 6β-hydroxycortisol. The therapeutic problems associated with enzyme inhibition have received much less attention than those associated with enzyme induction. The effect on the rate of elimination of a particular drug will depend upon the fraction of the dose that is normally metabolised by the inhibited enzyme and on the affinity of the enzyme for the drug and the inhibitor. An alteration in the dosage schedule is usually only necessary for drugs with a small therapeutic ratio.

Clinical Implications of Enzyme Induction and Enzyme Inhibition

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.510300205

Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: evidence for both genetic and environmental influences.

Glycemic control and prevention of secondary complications are the most important goals of using pharmacologic treatment of diabetes mellitus (DM). The inadequate responses to oral hypoglycemic agents may be attributed to inadequate postreceptor events even when insulin levels are quite sufficient, and associated with oxidative stress induced by long-term hyperglycemia. The administration of antioxidants such as melatonin and zinc may improve tissue responses to insulin and increase the efficacy of drugs, e.g. metformin, which act through this pathway. This project was designed to evaluate the effects of melatonin and zinc on the lipid profile and renal function in type 2 DM patients poorly controlled with metformin. A placebo-controlled, double-blind clinical trial was performed in which 46 type 2 diabetic patients were selected and allocated into three groups. These groups were treated with single daily oral doses of both 10 mg of melatonin and 50 mg of zinc acetate alone: 10 mg of melatonin and 50 mg of zinc acetate in addition to the regularly used metformin or placebo, given at bedtime for 90 days. Fasting lipid profiles and microalbuminuria (MAU) were measured before initiating the treatments (zero time) and after 30 and 90 days of treatment. Daily administration of melatonin and zinc improved the impaired lipid profile and decreased the level of MAU; the addition of this treatment regimen in combination with metformin improved the tissue responses to this oral hypoglycemic agent. In conclusion, the combination of melatonin and zinc acetate, when used alone or in combination with metformin, improves DM-related complications such as the impaired lipid profile and MAU in type 2 DM patients.

Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin

Abnormal Hepatic Transport of Indocyanine Green in Gilbert's Syndrome

1. The clearance of a tracer dose of [ 14 C]bilirubin from the plasma was studied in patients with Gilbert9s syndrome, congenital non-haemolytic jaundice, haemolytic jaundice and in normal subjects. Clearance was significantly impaired in the patients with Gilbert9s syndrome and in those with congenital non-haemolytic jaundice when compared with the normal subjects, and was normal in the patient with haemolytic jaundice. 2. Treatment for 2 weeks with phenobarbitone (180 mg/day) lowered the plasma bilirubin concentration and improved all indices of plasma clearance of the isotope in patients with Gilbert9s syndrome, so that they became indistinguishable from those of normal subjects. The improvement in plasma [ 14 C]bilirubin clearance in these patients was associated with modest increases in hepatic bilirubin glucuronyl transferase in some subjects. 3. Phenobarbitone treatment improved plasma bilirubin concentrations and plasma [ 14 C]bilirubin clearance in patients with congenital non-haemolytic jaundice, so that they resembled those seen in patients with untreated Gilbert9s syndrome. Despite this improvement hepatic bilirubin glucuronyl transferase activity remained undetectable. 4. These results are compatible with the hypothesis that Gilbert9s syndrome is a manifestation of a relative deficiency of hepatic bilirubin glucuronyl transferase, and differs from congenital non-haemolytic jaundice only in severity.

J. Jacobson

Papers

Effect of Phenobarbitone on Plasma [14C]Bilirubin Clearance in Patients with Unconjugated Hyperbilirubinaemia