Hepatic metabolism process

Renal/Hepatic function Impairment Excessive blood levels may result in patients with impaired liver or kidney function, including that caused by immature metabolic processes in the infant. 

Having access to metabolism data in the early discovery stage is invaluable. For example, hepatic metabolism data could be used to characterize the pharmacokinetic behavior of a perspective lead. Several studies have reported how metabolism databases and software systems have been used at various settings (272). In this section, we will provide an overview of recent databases, software systems, websites, tools, and services that could be potential starting points for metabolism modeling at various stages in drug discovery process (271,273). 

III.e.3.1. Hepatic disease. The liver, like the gut, has enormous redundancy and up to 80% of the organ can be removed without affecting many of its functions including most of the metabolic processes involved in the metabolism of drugs. 

Orally active agents used in the treatment of ED are more affected by aging and disease processes than are those injected intracavernosally. In addition, alterations in hepatic metabolism and/or renal clearance in the elderly man (see Chapter 6) influence the frequency of appearance of adverse reactions between several coadministered drugs in the treatment of ED. For example, the concomitant use of sildenafil and nitroglycerin is contraindicated by cardiovascular complications. Also, the use of testosterone in the presence of androgen-dependent tumors may promote tumor growth. 

This equation has a concentration term, C0, indicating that the half-life is variable and dependent on drug concentration. Changes in pharmacokinetic parameters that occur as a function of dose or drug concentration are referred to as nonlinear pharmacokinetic processes. Nonlinearity is usually due to saturation of protein binding, hepatic metabolism, or active renal transport of the drug.3... 

FIGURE 6.1 The barriers that a lipophilic drug has to transverse along the intestinal absorption process (1) dissolution and solubilization in the intestinal milieu, (2) narrow absorption window, (3) unstirred water layer, (4) efflux pumps, (5) intra-enterocyte metabolism, and (6) first pass hepatic metabolism. 

PK modeling can take the form of relatively simple models that treat the body as one or two compartments. The compartments have no precise physiologic meaning but provide sites into which a chemical can be distributed and from which a chemical can be excreted. Transport rates into (absorption and redistribution) and out of (excretion) these compartments can simulate the buildup of chemical concentration, achievement of a steady state (uptake and elimination rates are balanced), and washout of a chemical from tissues. The one- and two-compartment models typically use first-order linear rate constants for chemical disposition. That means that such processes as absorption, hepatic metabolism, and renal excretion are assumed to be directly related to chemical concentration without the possibility of saturation. Such models constitute the classical approach to PK analysis of therapeutic drugs (Dvorchik and Vesell 1976) and have also been used in selected cases for environmental chemicals (such as hydrazine, dioxins and methyl mercury) (Stem 1997 Lorber and Phillips 2002). As described below, these models can be used to relate biomonitoring results to exposure dose under some circumstances. 

The liver is a highly vascular structure which receives approximately 1.3 L of blood each minute. The blood supply originates from two sources 75 % is provided by the portal vein, which drains the gut, and the remainder is provided by the hepatic artery, which originates at the coeliac plexus of the aorta. These two blood supplies combine to provide the nutrient- and oxygen-rich blood necessary for the metabolic processes that occur in liver tissue. As a consequence the liver is perfectly placed within the circulation to gather and process metabolites and to eliminate toxins. 

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