Estimation from liver

HBV infection remains a major worldwide public health problem. The World Health Organization estimates that there are still 350 million chronic carriers of the vims, who are at risk of developing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The success of IFN-a treatment - mainly performed as combined treatment with adenine-arabinoside - has been measured by the normalization of liver enzymes, loss of HBe antigen and of detectable viral DNA in the serum of patients. It has been estimated from several clinical trials that as many as 40% of treated HBV patients would respond to therapy with IFN-a or combined treatment with nucleoside analogues and IFN-a. 

Chronic forms of hepatitis (in particular B, C and D) can result in liver cirrhosis and/or hepatocellular carcinoma. This occurs in up to 20 per cent of chronic hepatitis B sufferers and in up to 30 per cent of chronic hepatitis C sufferers. The scale of human suffering caused by hepatitis on a worldwide basis is enormous. Approximately 5 per cent of the global population suffer from chronic hepatitis B. An estimated 50 million new infections occur each year. Over 1.5 million of the 300 million carriers worldwide die annually from liver cirrhosis and hepatocellular carcinoma. 

Moving to toxic compounds, we encounter the infamous aflatoxin Bl, a mycotoxin considered to be a major cause of human liver cancer in some parts of the world. Thus, there are some estimates that, in China, as many as 1 in 10 adults die from liver cancer caused by aflatoxin [205]. Oxidation of... 

To make quantitative predictions of DDI for the new compound as perpetrator, a reliable estimate of a relevant in vivo concentration is needed. What is tmly needed is knowledge of the concentration of the inhibitor available to bind to the enzyme. For liver, if the well accepted free-dmg hypothesis (which underwrites fundamental drug action principles in pharmacology) is applied for DDI, then the use of a free intracellular liver concentration is needed. For inhibitors that are permeable through membranes, the free concentration in the portal vein should serve as the closest proxy for free intracellular concentration in the liver. Diminished permeability as well as active uptake and efflux from liver cells can confound this relationship. Nevertheless, use of estimates of unbound portal vein concentrations (which can be estimated from... 

The univariate response data on all standard biomarker data were analysed, ineluding analysis of variance for unbalaneed design, using Genstat v7.1 statistical software (VSN, 2003). In addition, a-priori pairwise t-tests were performed with the mean reference value, using the pooled variance estimate from the ANOVA. The real value data were not transformed. The average values for the KMBA and WOP biomarkers were not based on different flounder eaptured at the sites, but on replicate measurements of pooled liver tissue. The nominal response data of the immunohistochemical biomarkers (elassification of effects) were analysed by means of a Monte... 

Following administration to rat, dog, rabbit, and cow, clenbuterol was rapidly eliminated, being largely excreted in urine in the form of the parent drug (15). Following a 4 day treatment of cattle at the therapeutic dosage (0.8 g/kg bw) and a 7 day withdrawal, concentrations of clenbuterol in liver were at the level of 0.35 ppb or below, whereas concentrations in urine were approximately one-tenth of the levels in liver (16). Administration, on the other hand, of a single oral dose of radiolabeled clenbuterol to cattle showed that 40% of the urinary radioactivity was due to the parent compound. The urinary half-life of clenbuterol in cattle, estimated from the urinary excretion of the parent compound, was approximately 36 h (17). 

Keys et al. (1999) note that certain model parameter values were estimated by applying a step-wise parameter optimization routine to data on blood or tissue levels following oral or intravenous exposure to DEHP and MEHP. The parameters estimated included the km and Vmax values for metabolism of DEHP and MEHP, and first order rate constants for the following parameters metabolism of DEHP (e.g., liver), absorption of DEHP and MEHP in the small intestine, intracellular-to-extracellular transfer of nonionized MEHP, and biliary transfer of MEHP from liver to small intestine (these values are not provided in the profile because they are derived from optimization procedures and might not be directly useful for other models). Keys et al. (1999) do not explicitly cite or describe the data sets used to optimize model parameter values, or distinguish the data used in optimization from data used in validation exercises. Based on Table 5 of their report, it appears that at least some data from Pollack et al. (1985b) were used to optimize the model. 

Vmax and Km for MDZ 1 -liydroxylation. V,nax determined for each biopsy sample was then scaled to the estimated total liver mass and intrinsic clearance estimated as total liver Vmax/Kn- Hepatic clearance then was predicted from Equation 7.6 in Chapter 7. Figure 30.13 compares the observed total elimination clearance with predicted hepatic clearance based on the assumption that the E-hydroxylation pathway accounts for 70% of the substrate loss. The prediction is quite good. The average absolute deviation between the five observed data points and their predicted values is only 28% and the differences are uniformly distributed. 

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