Metabolism hepatic clearance

Let us take the exposure packages as an example technically, most of these assays are highly automated, require small amount of compounds and have a brief cycle time. Scientifically, they fulfill requirements to predict exposure by addressing the three major contributing factors solubility, passive permeability and metabolic (hepatic) clearance. These type of packages are ideal to explore or diagnose scaffold characteristics and define project flowcharts. They can be used repeatedly to test newly synthesized compounds and guide SAR. A number of compounds within a... 

An important DMPK property of a NCE is oral bioavailability (F) of the compound in various pre-clinical species.3 The oral bioavailability of a compound is dependent on several factors including intestinal permeability (estimated by the Caco-2 assay) and hepatic clearance (estimated with an in vitro metabolic stability assay).3 30 The metabolic stability assay is typically performed by incubating test compounds in liver microsomes or hepatocytes. The results can provide estimates of in vivo stability in terms of metabolic liabilities.3 8 59 62 Several authors described this assay as an important tool for the rapid assessment of the DMPK properties of NCEs.3 6 8111819 26 44 59 62-65... 

The species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance of esfenvalerate and deltamethrin using rat and human liver microsomes were examined [33]. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The CLint of esfenvalerate was estimated to be threefold greater in rodents than in humans on a per kg body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes however, in human liver microsomes, deltamethrin was eliminated almost entirely via... 

Thus, for example, if a chemical is eliminated only by renal excretion and hepatic metabolism, total clearance is a composite... 

S. Suzuki, A. Kagayama, A. et ah Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab Dispos 2001, 29, 1316-1324. 

The organs of extraction are generally the liver (hepatic clearance - metabolism and biliary excretion CIh) and the kidney (renal excretion, CIr) and the values can be summed together to give an overall value for systemic clearance (Cls) ... 

Compound A appears mainly as unchanged drug in the bile whereas compound B appears partly as metabolites. Administration of ketoconazole, a potent cytochrome P450 inhibitor, to the preparation dramatically decreases the metabolism of B and the compound appears mainly as unchanged material in the bile. Despite the inhibition of metabolism, hepatic extraction remains high (0.9). This indicates that clearance is dependent on hepatic uptake, via a transporter system, for removal of the compounds from the circulation. Metabolism of compound B is a process that occurs subsequent to this rate-determining step and does not influence overall clearance. This model for the various processes involved in the clearance of these compounds is illustrated in Figure 5.4. 

Lewis, D. F. and Dickins, M. (2002) Factors influencing rates and clearance in P450-mediated reactions QSARs for substrates of the xenobiotic-metabolizing hepatic microsomal P450s. Toxicology 170, 45-53. 

The analysis was completed for 12 compounds for which protein binding, renal and hepatic clearances and microsomal data were available. Plasma concentration versus time profiles in the rat were also available for these compounds. The approach taken was to simulate the individual processes (metabolic clearance, renal clearance, distribution, pharmacological activity). The ability of the PBPK model to simulate the in vivo behavior of the compound was verified in the rat. Thus, the metabolic clearance of the compounds could be reasonably well simulated, based on microsomal data and assuming no binding to microsomes less than twofold deviation between the observed and predicted clearance was achieved for about eight of the... 

B. Perfusion of the brain is preserved when hemorrhage occurs. Thus, a greater proportion of the initial dose of anesthetic should appear in the brain, and a dose smaller than what is needed for a normovolemic patient is all that is required. Also, since flow to tissues associated with redistribution of the drug and termination of anesthesia is compromised, anesthesia should be deep and extended. Titrate this patient to a safe level of effect. While poor perfusion of the liver may reduce the exposure of drugs to metabolic enzymes, most intravenous anesthetics rely very little on hepatic clearance to terminate the anesthetic effect when a single bolus is administered. Furthermore, the question implies a direct influence of blood pressure on the efficiency of hepatic enzymes, and there is no evidence to support such a contention. Option C is not true. The opposite of option D is true. No evidence exists that binding of anesthetics is altered by these conditions. 

Metabolism and clearance of buspirone is decreased with hepatic cirrhosis and renal disease (Gammans et ah, 1986). 

Some drugs are metabolized so readily that even marked reduction in liver function does not significantly prolong their action. However, cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited (Table 4-7). These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. Pulmonary disease may also affect drug metabolism, as indicated by the impaired... 

Table 4-7 Rapidly Metabolized Drugs Whose Hepatic Clearance Is Blood Flow-Limited. ...

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