Bilirubin metabolism/excretion, drugs

This patient shows a cholestatic picture with a raised bilirubin and alkaline phosphatase. In terms of drug handling this may cause reduced absorption of some lipid-soluble drugs and impaired elimination of biliary excreted drugs. The ALT is raised but synthetic function is maintained, as indicated by a normal INR and albumin. This snggests that the hepatocytes are working effectively and therefore the metabolic function of the liver is unlikely to be altered in this patient. 

Interference with bilirubin metabolism and excretion. Jaundice is induced selectively with minimal or no disturbance of other liver function tests recovery ordinarily occurs on stopping the drug. Examples are ... 

The sinusoids transport both portal and arterial blood to the hepatocytes. The systemic blood delivered to the liver contains nutrients, drugs, and ingested toxins. The liver processes the nutrients (carbohydrates, proteins, lipids, vitamins, and minerals) for either immediate use or for storage, while the drugs and toxins are metabolized through a variety of processes known as first-pass metabolism. The liver also processes metabolic waste products for excretion. In cirrhosis, bilirubin (from the enzymatic breakdown of heme) can accumulate this causes jaundice (yellowing of the skin), scleral icterus (yellowing of the sclera), and tea-colored urine (urinary bilirubin excretion). 

Metabolism and excretion of certain drugs, bilirubin, and hormones... 

Plasma bilirubin may be increased due to drug-related inhibition of uridine diphosphate glucuronosyltransferase (Zucker et al. 2001) or inhibitors of hepatic bilirubin transporters. By contrast, plasma bilirubin concentration may fall following administration of some mixed-function oxidase inducers, which may enhance the metabolism and excretion of bilirubin. 

The liver extensively metabolizes all three agents, and the conjugates and metabolites are excreted in the bile. Only a small fraction of a dose (<15%) is found in the urine unchanged. In patients with hepatic dysfunction (bilirubin >3 mg/dL), a 75% reduction in dose of any of the vinca alkaloids is advisable. The pharmacokinetics of each of the three drugs are similar, with central and tissue elimination half-lives of 1 and 20 hours for vincristine, 3 and 23 hours for vinblastine, and 1 and 45 hours for vinorelbine, respectively. 

Daunorubicin, doxorubicin, epirubicin, and idarubicin usually are administered intravenously. Careful infusion over 10-15 minutes is recommended to prevent extravasation, since severe local vesicant action may result. The drugs are cleared by a complex pattern of hepatic metabolism and biliary excretion. The plasma disappearance curve for doxorubicin is multipha-sic, with elimination half-lives of 3 hours and - SO hours. All anthracyclines are converted to an active alcohol intermediate that plays a variable role in their therapeutic activity. Idarubicin has a tj of 15 hours, and its active metabolite, idarubicinol, has a tj of - 40 hours. There is rapid upt e of the drugs in the heart, kidneys, lungs, liver, and spleen. They do not cross the blood-brain barrier. Daunorubicin and doxorubicin are eliminated by metabolic conversion to a variety of aglycones and other inactive products. Idarubicin is primarily metabolized to idarubicinol, which accumulates in plasma and likely contributes significantly to its activity. Clearance is delayed in the presence of hepatic dysfunction, and at least a 50% initial reduction in dose should be considered in patients with elevated serum bilirubin levels. 

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