Hepatic Metabolic Function

Williams, S.J., Farrell, G.C. Serial antipyrine clearance studies defect altered hepatic metabolic function during spontaneous and interferon-induced changes in chronic hepatitis B disease activity. Hepatology 1989 10 192-197... 

Mexifitene is well absorbed from the GI tract and less than 10% undergoes first-pass hepatic metabolism. In plasma, 60—70% of the dmg is protein bound and peak plasma concentrations are achieved in 2—3 h. Therapeutic plasma concentrations are 0.5—2.0 lg/mL. The plasma half-life of mexifitene is 10—12 h in patients having normal renal and hepatic function. Toxic effects are noted at plasma concentrations of 1.5—3.0 lg/mL, although side effects have been noted at therapeutic concentrations. The metabolite, /V-methy1mexi1itene, has some antiarrhythmic activity. About 85% of the dmg is metabolized to inactive metabolites. The kidneys excrete about 10% of the dmg unchanged, the rest as metabolites. Excretion can also occur in the bile and in breast milk (1,2). 

By enhancing the metabolism of trichloroethylene to its cytotoxic metabolites, compounds that induce the hepatic mixed-function oxidase system can potentiate the hepatotoxicity of trichloroethylene. 

L The answer is d. (Hardman, p 906.) Cimetidine slows the metabolism of Ca channel blockers, which are substrates for hepatic mixed-function oxidases. Inhibition of cytochrome P450 activity is peculiar to cimetidine and is not a mechanism of action of other histamine 2 (Hz) blockers. 

Metabolism Hepatic metabolism may be reduced Decreased hepatic blood flow. Decreased liver mass. Diminished enzymatic function Important for some drags Verapamil and teophylline... 

Robertson P, White EL, Bus JS. 1989. Effects of methyl ethyl ketone pretreatment on hepatic mixed-function oxidase activity and on in vivo metabolism of -hexane. Xenobiotica 19(7) 721-729. 

Molinate Metabolism in Carp Hepatic Mixed-function Oxidase System. Incubation of molinate with carp liver microsomes produced four major organosoluble metabolites (molinate sulfoxide, 3- and 4-hydroxy molinate, and keto HMI). Parameters affecting... 

Hepatic mixed-function oxidase activities demonstrated seasonal trends, with higher specific activities in the cold weather months in both populations with few differences in enzyme activities or cytochrome levels between the two populations. Metabolism of aldrin, dieldrin and DDT was similar between the two populations. R fish have larger relative liver size and, therefore, a greater potential for xenobiotic metabolism. However, biotransformation appears to be of minor importance in chlorinated alicyclic insecticide resistance in mosquitofish barriers to penetration appear to be of greater importance and an implied target site insensitivity appears to be the most important factor in resistance. 

Renal/hepatic function impairment In general, patients with renal failure will require the usual doses of mexiletine. Patients with severe liver disease, however, may require lower doses and must be monitored closely. Similarly, marked right-sided CHF can reduce hepatic metabolism and reduce the dose needed. 

Hepatic function impairment Administer doxazosin and alfuzosin with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism. 

Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal. 

Hepatic function impairment- Because zidovudine is primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these patients. Frequent monitoring for hematologic toxicities is advised. 

Warfarin has hccn drlcrmiiicd from plasma 3f>7). Siinlics of iis metabolic fate due to the action of hepatic mixed function oxidases have profited from the use of reversed-phase columns for the determination of metabolites (368). Related studies on warfarin resistance have utilized vitamin Kt 2,3-epoxide to examine the rate of its reduction in rats to form X ilamin h the rraxMion was follitwcil x liromalxtitrapliii allv... 

II.f.2.2. Sulphonylureas. These drugs stimulate pancreatic /3-cell insulin secretion, reduce serum glucagon levels, potentiate insulin action on target tissues, and improve /3-cell function. The sulphonylureas differ in their potency, extent of hepatic metabolism, hypoglycaemic activity of their metabolites, renal excretion, peak and duration of action, side effects and costs. 

Roughly half of an orally administered dose of atenolol (Tenormin) is absorbed. The drug is eliminated primarily by the kidney and unlike propranolol, undergoes little hepatic metabolism. Its plasma half-life is approximately 6 hours, although if it is administered to a patient with impaired renal function, its half-life can be considerably prolonged. 

Cimetidine binds to cytochrome P-450 hepatic mixed-function oxidase enzymes. This leads to enzyme inhibition and reduced metabolism of... 

Acute or chronic diseases that affect liver architecture or function markedly affect hepatic metabolism of some drugs. 

Treatment of ethanol withdrawal is supportive and relies on benzodiazepines, taking care to use compounds such as oxazepam and lorazepam, which are not as dependent on hepatic metabolism as most other benzodiazepines. In patients in whom monitoring is not reliable and liver function is adequate, a longer-acting benzodiazepine such as chlordiazepoxide is preferred. 

Because its clearance depends on renal function as well as hepatic metabolism, diflunisal s dosage should be limited in patients with significant... 

Proton pump inhibitors undergo rapid first-pass and systemic hepatic metabolism and have negligible renal clearance. Dose reduction is not needed for patients with renal insufficiency or mild to moderate liver disease but should be considered in patients with severe liver impairment. Although other proton pumps exist in the body, the H+,K+ ATPase appears to exist only in the parietal cell and is distinct structurally and functionally from other H+ -transporting enzymes. 

The liver is involved in a variety of both synthetic and catabolic functions, including metabolism of amino acids, lipids, carbohydrates, protein synthesis and detoxification [ 1 ]. These metabolic functions are performed mainly by hepatocytes, although the liver is made of three major cell types (hepatocytes, biliary epithelial cells and Kupffer cells). Exerting many different metabolic functions, the liver contains several different and specific enzymes, leakage of which into the bloodstream occurs in hepatic diseases. 

One design requirement is to provide a physical scaffold that permits near-normal proliferation of cells. Proliferation is encouraged by scaffold with an open and curvilinear structure — a more or less natural conformation. For example, hepatic cells cultured on a flat plate do not function. The cell survival signals are functional as evidenced by our ability to keep cells alive, but their metabolic functions are destroyed when they are forced into a flat conformation. By inference, therefore, a concave structure is thought to be appropriate. As cells migrate to coat a surface, it is equally important to provide a scaffold that has as open an architecture as possible so as not to inhibit spreading. 

FIGURE 7.4 Hepatic spheroid in structure of polyurethane foam. (From Yamashita, Y. et ah, High Metabolic Function of Primary Human and Porcine Hepatocytes, Cell Transplantation, Vol. 11, pp. 379-384, 2002.)... 

Woo, Y.T., Argus, M.F. Arcos, J.C. (1977b) Metabolism in vivo of dioxane effect of inducers and inhibitors of hepatic mixed-function oxidases. Biochem. Pharmacol., 25, 1539-1542 Woo, Y.T., Argus, M.F. Arcos, J.C. (1978) Effect of mixed-function oxidase modifiers on... 

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... 

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