Cholestasis drug-induced

Chlorpromazine Cholestasis (drug-induced) Imipramine Carbarsone... 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Alkaline phosphatase levels and GGT are elevated in plasma with obstructive disorders that disrupt the flow of bile from hepatocytes to the bile ducts or from the biliary tree to the intestines in condition such as primary biliary cirrhosis, sclerosing cholangitis, drug-induced cholestasis, gallstone disease, and autoimmune cholestatic liver disease. 

Sakurai, A., Kurata, A., Onishi, Y., Hirano, H. and Ishikawa, T. (2007) Prediction of drug-induced intrahepatic cholestasis ... 

Inhibition ofBiie Sait Ejfiux Protein and Drug-Induced Cholestasis 365... 

Inhibition of Bile Salt Efflux Protein and Drug-Induced Cholestasis... 

In vivo, measuring bile acids in plasma and urine should be revived as potential biomarkers in the modern metabolomic era. Then the first-order scientific question will become whether early and time-controlled fasting-level measurement of bile acid concentration in plasma and urine can become a sensitive and specific biomarker for drug-induced cholestasis and ultimately liver injury at later time-points [117] Clinical trials should be conducted to evaluate whether such bile acid measurements can be used as part of a predictive panel to identify patients who are at increased risk of drug-induced cholestasis. 

Critical Review Is There a Link between BSEP Inhibition, Drug-Induced Cholestasis and Idiosyncratic Liver Injury ... 

The best clinical evidence that BSEP is involved in hepatotoxicity is provided by human genetic studies which found four highly conserved non-synonymous mutations in two hepatobiliary transporters (BSEP and MDR3) that were specific for drug-induced liver injury [118]. Recently, a consortium of investigators identified a remarkable 82 different ABCBll mutations in 109 families that caused severe BSEP deficiency [119]. It is therefore expected that at least some of these genetic mutations and polymorphisms will put patients at an increased risk of drug-induced cholestasis. Does this justify the implementation of a simple BSEP inhibition screen for all new chemical entities The answer is not quite that simple. 

Pauli-Magnus, C. and Meier, P.J. (2006) Hepatobiliary transporters and drug-induced cholestasis. Hepatology (Baltimore, Md), 44 (4), 778-787. 

Dose-independent, drug-induced liver dysfunction (cholestatic jaundice) is not an unusual adverse reaction. Caused by a number of different, commonly used drugs, cholestasis is a hypersensitivity reaction that primarily affects the biliary canaliculi, causing an intrahepatic obstructive jaundice. An alteration in... 

A biopsy is often required to make a diagnosis of most types of liver disease. A specimen of liver can be used to identify fibrosis, cirrhosis, cholestasis and hepatitis, both acute and chronic, and tumours. Biochemical measurements can also be taken from a biopsy specimen to determine iron and copper content, virology, microbiology and haematology (e.g. increased numbers of eosinophils in a drug-induced cause). The biopsy can give an indication of the extent of the liver damage. See Chapter 3 for slides of liver biopsies. 

Weden [27] described a protracted cholestasis which was thought to be induced by the use of a COC. The patient s liver biopsy revealed changes including eosinophilia and sinusoidal dilatation, which could be linked to a drug-induced liver injury. The cholestasis gradually disappeared, but an elevated serum alkaline phosphatase level continued for up to ten years after discontinuation of the COC [27]. Another paper has discussed oestrogen-induced cholestasis and highlights the link between the use of COCs and intrahepatic cholestasis... 

Pomiersky C, Blaich E. Arzneimittelbedingte Hepatitis mit Cholestase nach Therapie mit Chlormezanon.. [Drug-induced hepatitis with cholestasis following therapy with chlormezanone.] Z Gastroenterol 1985 23(12) 684-6. 

Drug-induced cholestasis has rarely been reported in patients taking cinnarizine. 

Fatal drug-induced cholestasis associated with clarithromycin 500 mg bd for 3 days has been reported in a 59-year-old woman with diabetes mellitus and chronic renal insufficiency (39). 

Fatal cholestatic hver failure occurred in a 45-year-old woman with metastatic breast cancer who was given gemcitabine and carboplatin and pre-existing liver damage. After four courses of gemcitabine -I- carboplatin she developed severe decompensated cholestatic hepatitis (9). Liver biopsy showed marked cholestasis and hepatocellular injury consistent with drug-induced hepatotoxicity. 

Cholestatic hepatitis occurred in an 83-year-old man after 9 months of continuous therapy with moxonidine. No autoantibodies were detected and liver biopsy showed features compatible with drug-induced inflammatory intrahepatic cholestasis. The patient recovered fully and his biochemical data normalized 8 weeks after withdrawal. 

Chitturi S, Farrell GC. Drug-induced cholestasis. Semin Gastrointest Dis 200I I2(2) 113-24. 

Hirano H, Kurata A, Onishi Y, Sakurai A, Saito H, Nakagawa H, et al. High-speed screening and QSAR analysis of human ATP-binding cassette transporter ABCB11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis. Mol Pharm 2006 3 252-65. 

Zimmerman H, Lewis J. Drug-induced cholestasis. Med Toxicol 1987 2 112-60. 

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