In hepatitis

Intestinal absorption of digoxin is less complete compared to digitoxin. In order to improve absorption, acetylated- and methylated-digoxin derivates were developed. Digitoxin is metabolised in hepatic microsomal enzymes and can be cleared independently from renal function. The therapeutical serum level of digoxin is 0.5-2.0 ng/ml and 10-35 ng/ml of digitoxin. Steady state plateau of therapeutic plasma concentrations is reached after 4-5 half-life-times using standard daily doses [5]. 

FATP5 KO mice have been characterized in two studies focusing on the role of FATP5 in hepatic lipid and bile metabolism. LCFA uptake in primary hepato-cytes isolated from FATP5 KO mice was reduced by 50% and hepatic lipid content in the KO mice was significantly reduced despite an increased fatty acid de novo biosynthesis. Detailed analysis of the hepatic lipidome of FATP5 KO mice revealed significant... 

PYRAZINAMIDE Patients should have baseline liver functions tests to use as a comparison when monitoring liver function during pyrazinamide therapy. The nurse should monitor the patient closely for symptoms of a decline in hepatic functioning (ie, yellowing of the skin, malaise, liver tenderness, anorexia, or nausea). The primary health care provider may order periodic liver function tests. Hepatotoxicity appears to be dose related and may appear at any time during therapy. 

Chick J, Lehert P, Landron F, et al Does acamprosate improve reduction of drinking as well as aiding abstinence J Psychopharmacol 17 397-A02, 2003 Chrostek L, Jelski W, Szmitkowski M, et al Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans. J Clin Lab Anal 17 93-96, 2003... 

Di Marco S, Volpari C, Tomei L, Altamura S, Harper S, Narjes F, Koch U, Rowley M, De Francesco R, Mighaccio G, Card A (2005) Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J Biol Chem 280 29765-29770... 

Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J, McNair L, Purdy S, Kauffman R, Alam J, Jansen PL (2006) Rapid decline of viral RNA in hepatitis C patients treated with VX-950 a phase Ib, placebo-controUed, randomized study. Gastroenterology 131 997-1002... 

Shi M, Wang RS, Zhang H, Zhu YF, Han B, Zhang Y, Jin LJ, Yang ZJ, Xu YP (2006) Sequential treatment with lamivudine and interferon-alpha monotherapies in hepatitis B e antigennegative Chinese patients and its suppression of lamivudine-resistant mutations, J Antimicrob Chemother 58 1031-1035... 

Nowak MA, Bonhoeffer S, HiU AM, Boehme R, Thomas HC, McDade H (1996) Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci USA 93 4398 402... 

Table 2 Clinical management of antiviral resistance in hepatitis B (modified according to Lok and McMahon (2007))...

Diago M, Hassanein T, Rodes J, Ackrill AM, Sedarati F (2004) Optimized virologic response in hepatitis C virus genotype 4 with peginterferon-alpha2a and ribavirin. Ann Intern Med 140(l) 72-73... 

HavUr DV, Richman DD (1996) Viral dynamics of HIV implications for drug development and therapeutic strategies. Ann Intern Med 124(11) 984—994 Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL, Foms X, Erhardt A, Cronlein J, Chaves RL, Yong CL, Nehmiz G, Steinmann GG (2004) Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype I patients. Gastroenterology 127(5) 1347-1355... 

Mihm U, Herrmann E, Sarrazin C, Zeuzem S (2006) Review article predicting response in hepatitis C virus therapy. Aliment Pharmacol Xher 23(8) 1043-1054 Pawlotsky JM (2005) Current and future concepts in hepatitis C therapy. Semin Liver Dis 25(l) 72-83... 

Evidence suggests that endosulfan can induce microsomal enzyme activity. Increased liver microsomal cytochrome P-450 activity was observed in male and female rats after single and multiple administrations of endosulfan (Siddiqui et al. 1987a Tyagi et al. 1984). Increased enzyme activity was observed in hepatic and extrahepatic tissues. Based on the increase in aminopyrine-A-demethylase and aniline hydroxylase activity, endosulfan has been shown to be a nonspecific inducer of drug metabolism (Agarwal et al. 1978). 

Siddiqui MKJ, Anjum F, Qadri SSH. 1987a. Some metabolic changes induced by endosulfan in hepatic and extra hepatic hssues of rat. J Environ Sci Health B22 553-564. 

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

The ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) are formed in hepatic mitochondria when there is a high rate of fatty acid oxidation. The pathway of ketogenesis involves synthesis and breakdown of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-CoA synthase and HMG-GoA lyase. 

ALA Synthase Is the Key Regulatory Enzyme in Hepatic Biosynthesis of Heme... 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

This is a rare benign condition characterized by chronic conjugated hyperbilirubinemia and normal liver histology. Its precise cause has not been identified, but it is thought to be due to an abnormality in hepatic storage. 

The commonest causes of obstructive (posthepatic) jaundice are cancer of the head of the pancreas and a gallstone lodged in the common bile duct. The presence of bilirubin in the urine is sometimes referred to as choluria—therefore, hepatitis and obstruction of the common bile duct cause choluric Jaundice, whereas the Jaundice of hemolytic anemia is referred to as acholuric. The laboratory results in patients with hepatitis are variable, depending on the extent of damage to parenchymal cells and the extent of micro-obstruction to bile ductules. Serum levels of ALT and AST are usually markedly elevated in hepatitis, whereas serum levels of alkaline phosphatase are elevated in obstructive liver disease. 

The cytochrome P-450-dependent metabolism of trichloroethylene was studied in hepatic microsomal fractions from 23 different humans (Lipscomb et al. 1997). CYP2E1 was the predominant form of P-450 responsible for the metabolism of trichloroethylene in humans. Incubations of trichloroethylene with the microsomal preparations resulted in hyperbolic plots consistent with Michaelis-Menton kinetics. The values ranged from 12 to 55.7 pM, and were not normally distributed, and the values range from 490 to 3,455 pmol/min/mg protein and were normally distributed. The study authors concluded that the human variability in metabolism of trichloroethylene via P-450-dependent pathways was within a 10-fold range. 

Klaunig et al. (1991) found that hepatocyte DNA synthesis increased significantly in male mice exposed to trichloroethylene by gavage for up to 14 days, but no such increase was seen in female mice or in renal DNA synthesis in either sex. Similar exposures in rats produced increases in renal DNA synthesis in males, but no such increase in females, or in hepatic DNA synthesis in either sex. These results correlate well with observed species- and gender-specific trichloroethylene carcinogenicity, and the study authors suggest that trichloroethylene acts as a tumor promoter to induce proliferation of previously initiated cells. 

Garcea, G. et al.. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration, Br. J. Cancer, 90, 1011, 2004. 

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