Liver, metabolism

Hue, L. Van de Werve, G. (eds.) (1981). In Short-Term Regulation of Liver Metabolism. El-sevier/North Holland Biochemical Press, Amsterdam. 

There are several pharmacokinetic differences between loop diuretics. Fifty to sixty percent of a dose of furosemide is excreted unchanged by the kidney with the remainder undergoing glucuronide conjugation in the kidney.17 In contrast, liver metabolism accounts for 50% and 80% of the elimination of bumetanide and torsemide, respectively.17 Thus, patients with ARF may have a prolonged half-life of furosemide. The bioavailability of both torsemide and bumetanide is higher than for furosemide. The intravenous (IV) oral ratio for bumetanide and torsemide is 1 1, bioavailability of oral furosemide is approximately 50%, with a reported range of 10% to 100%.18... 

The therapeutic dose of acamprosate is 666 mg orally three times daily, and it is supplied as a 333 mg tablet. It can be started at the full dose in most patients without titration. It differs from disulfiram and naltrexone in that it is excreted by the kidneys without liver metabolism. Consequently, it is contraindicated in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/minute), and dose reduction is necessary when the creatinine clearance is between 30 and 50 mL/minute. The most common side effects are gastrointestinal and include nausea and diarrhea. Rates of suicidal thoughts were also increased in patients treated for 1 year with acamprosate (2.4%) versus placebo (0.8%). If necessary the total daily dose maybe decreased by 1 to 3 tablets (333-999 mg) per day to alleviate side effects. 

Mitomycin C is an alkylating agent that forms cross-links with DNA to inhibit DNA and RNA synthesis. The pharmacokinetics of mitomycin C are best described by a two-compartment model, with an a half-life of 8 minutes and a terminal half-life of 48 minutes.31 Liver metabolism is the primary route of elimination. Mitomycin C has shown clinical activity in the treatment of anal, bladder, cervix, gallbladder, esophageal, and stomach cancer. Side effects consist of myelosuppression and mucositis, and it is a vesicant. 

Liver metabolism is affected by methylxanthines. In high doses, theophylline and caffeine increase the level of cyclic AMP. Very high levels of methylxanthines decrease the level of branched chain and aromatic amino acids in plasma. Coffee appears to have little effect on ethanol metabolism. 

The pharmacist should certainly know which drug dosage forms have been designed as delivery systems for prodrugs and also understand the mechanism whereby the active form is made available within the body. Only then can the pharmacist counsel the physician about why a certain product may be inappropriate for such individuals as an achlorhydric patient, a patient with a gastrectomy, or even possibly a patient with a hepatoportal bypass, if liver metabolism... 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

Alcohol intake Induction of liver-metabolism during chronic alcohol intake... 

Hepatic insufficiency Decrease of liver metabolism, leading to increased efficacy of warfarin... 

The liver metabolizes 98% to 99% of a dose of carbamazepine (mostly by CYP3A4), and the major metabolite is carbamazepine-10,11-epoxide, which is active. 

Robinson KM, Yarbrough JD. 1978b. A study of mirex induced changes in liver metabolism and function with emphasis on liver enlargement. Fed Proc, Fed Am Soc Exp Biol 37 699. 

The main organ involved in PCB metabolism and excretion in fish is the liver. Metabolism of PCBs in fish liver homogenates has been demonstrated (29,30,32) and PCB metabolites are excreted into bile (25,28,34). What is not known is extent to which PCB metabolites excreted in bile are eliminated in feces. Also the role of kidneys, gills, intestine and skin in PCB elimination in fish has not been fully elucidated. The only study on urinary excretion of PCBs was in dogfish sharks and revealed that urine was not a major route of elimination (28). 

Stilbene oxide (2,3-diphenyloxirane) is another compound of interest. It exists as two diastereoisomers, namely cA-stilbene oxide (10.7, Fig. 10.28) and the trans-(RJi)- and /ra/i.y-(5,5)-stilbene oxides (10.121, Fig. 10.28), which exhibit significant but condition-dependent substrate selectivity. Cytosolic EH purified from mouse liver metabolized racemic tram -sti I bene oxide with high affinity and high velocity, and cA-stilbene oxide with lower affinity and lower... 

Drugs absorbed through the gastrointestinal tract pass into the hepatic portal vein, which drains into the liver. The liver metabolizes the drug, which leads to reduction in the availability of the drug for interaction with receptors. This is called first pass metabolism. A schematic representation of the process of drug in the body is given in Fig. 5.7. 

O Ketoacidosis is a dangerous condition that is characterized by the acidification of the blood and an acetone odour on the breath. The condition occurs when levels of oxaloacetic acid for the citric acid cycle are low. This leads to a buildup of acetyl CoA molecules, which the liver metabolizes to produce acidic ketone bodies. Since carbohydrates are the main source of oxaloacetic acid in the body, high-protein, low-carbohydrate diets have been linked to ketoacidosis. 

Each hormone is the center of a hormonal regulation system. Specialized glandular cells synthesize the hormone from precursors, store it in many cases, and release it into the bloodstream when needed (biosynthesis). For transport, the poorly water-soluble lipophilic hormones are bound to plasma proteins known as hormone carriers. To stop the effects of the hormone again, it is inactivated by enzymatic reactions, most of which take place in the liver (metabolism). Finally, the hormone and its metabolites are expelled via the excretory system, usually in the kidney (excretion). All of these processes affect the concentration of the hormone and thus contribute to regulation of the hormonal signal. 

Metabolism/Excretion-The liver metabolizes 80% to 92% of the drug the remainder is excreted unchanged in the urine. Excretion is mainly renal (90%), with less than 10% appearing in feces. 

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