Xenobiotics, hepatic clearance

The volume of biological fluid totally cleared of xenobiotic per unit time and usually includes hepatic clearance and renal clearance. 

B. A. Hoener, Predicting the hepatic-clearance of xenobiotics in humans from in-vitro data. Biopharm Drug Dispos 15 295-304 (1994). 

Clearance tests of liver function assess a number of physiologic activities including hepatic uptake, hepatic metabolism, and hepatic excretion. Typical clearance tests of liver function include indocyanine green (ICG), antipyrine clearance test and C aminopyrine breath test. These tests give an estimation of the ability of the liver to extract and detoxify exogenous toxins (xenobiotics). Measuring the excretion of endogenously produced serum bile acids is an additional measure of hepatic clearance and has been used as a sensitive measure of early solvent hepatotoxicity." "... 

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 extent to which the liver successfully eliminates a xenobiotic from the blood is determined by the intrinsic clearance of the liver (Clh) and the rate at which the xenobiotic is presented to it (i.e., the hepatic blood flow Qh ). This gives the overall hepatic extraction ratio (E) for the compound, as shown in Equation 11.3 ... 

Clearance (CL) Clearance represents the volume of blood (e.g., milliliter and liter) that is completely cleared of a xenobiotic during a given period of time, usually 1 min or 1 h (e.g., ml min 1 h ). As such, the clearance is a quantitative measure of the rate of removal of a compound from the body. All routes of elimination (e.g., hepatic biotransformation, urinary, biliary, and pulmonary excretion) contribute to the clearance of a chemical from the body, and each one... 

A cholesterol ester forms In the liver of rats given an oral dose (250 mg/kg for seven days) of the hypolipidemic drug l-(4-carboxyphenoxy)-10-(4-chlorophenoxy)decane ( 2J ). This xenobiotic cholesterol ester represented about 11% of the total lipid In the liver and was neither further metabolized nor transported by lipoproteins. An additional 1% of the total liver lipids consisted of hybrid trlacylglycerols containing this xenobiotic. The authors of this work suggest that the hypocholesterolemlc activity of the drug In rats results from hepatic accumulation of the xenobiotic cholesterol ester which appears to promote the hydrolysis of natural cholesterol esters and thereby facilitate clearance of low-density lipoproteins. 

Substances influencing drug and xenobiotic metabolism (other than enzyme inducers) include lipids, proteins, vitamins, and metals. Dietary lipid and protein deficiencies diminish microsomal drug-metabolizing activity. Protein deficiency leads to a reduction in hepatic microsomal protein and lipid deficiency oxidative metabolism is decreased because of an alteration in endoplasmic reticulum (ER) membrane permeability affecting electron transfer. In terms of toxicity, protein deficiency would increase the toxicity of drugs and xenobiotics by reducing their oxidative microsomal metabolism and clearance from the body. 

Sober alcoholics show an increase in CYP2E1 enzyme activity, leading to more rapid clearance of drugs and xenobiotics that are substrates for this isoform from the body. As discussed previously, hepatic CYP2E1... 

Age. Absorption and first-pass metabolism of phytochemicals may be age-dependent, thus neonates exhibit reduced hepatic metabolism and renal excretion as a direct consequence of the immaturity of liver and kidney function. The susceptibility of the elderly to xenobiotics may be affected by age-related alterations in absorption, intestinal and hepatic metabolism, renal clearance, or volume of distribution [27]. 

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