Hepatic elimination

Aside from gastrointestinal and renal metabolism, the liver may also contribute substantially to the metabolism of peptide and protein drugs. Proteolysis usually starts with endopeptidases that attack in the middle part of the protein, and the resulting oligopeptides are then further degraded by exopeptidases. The ultimate metabolites of proteins, amino acids and dipeptides, are finally reutilized in the endogenous amino acid pool. The rate of hepatic metabolism is largely dependent on specific amino acid sequences in the protein. 

Substrates for hepatic metabolism include insulin, glucagon, and t-PAs [89,90]. For insulin, an acidic endopeptidase (termed endosomal acidic insulinase ) appears to mediate internalized insulin proteolysis at a number of sites [91]. Specifically, the endosomal activity results from cathepsin D, an aspartic acid protease [92]. Similarly, proteolysis of glucagon has also been attributed to membrane-bound forms ofcathepsins B and D [93]. 

An important first step in the hepatic metabolism of proteins and peptides is uptake into the hepatocytes. Small peptides may cross the hepatocyte membrane via passive diffusion if they have sufficient hydrophobicity. Uptake of larger pro- 

The kidneys are a common site of chemical toxicity since the nephron functions to concentrate the toxicant and thus increase levels of exposure to the materials. This increased exposure can result from the concentration of the toxicant in the tubules. It also can occur by concentration within the cells of the nephrons when a chemical is capable of utilizing one of the active transport proteins and is shuttled from the lumen of the tubules into the renal cells. 

Passive diffusion, carrier-mediated, or active transport across sinusoidal membrane 

Intracelluluar transfer in association with binding proteins 

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Yamazaki, M., Akiyama, S., Nishigaki, R., Sugiyama, Y., Uptake is the rate-limiting step in the overall hepatic elimination of pravastatin at steady-state in rats, Pharm. Res. 1996, 13, 1559-1564. 

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

This use of Equation 9.10 to relate AUCpo to kdeg is valid under the assumption that only hepatic elimination occurs, well-stirred model conditions and complete absorption occurs in the GI tract. 

Fusidic acid is a narrow-spectrum, antibacterial agent that relies on hepatic elimination. No cautionary action is recommended for patients with renal impairment. 

Hepatic elimination obeys exponential kinetics because metabolizing enzymes operate in the quasilinear region of their concentration-activity curve hence the amount of drug metabolized per unit of time diminishes with decreasing blood concentration. 

The natural hormones are unsuitable for oral application because they are subject to presystemic hepatic elimination. Estradiol is converted via estrone to estriol by conjugation, all three can be rendered water soluble and amenable to renal excretion. The major metabolite of progesterone is pregnandiol, which is also conjugated and eliminated renally. 

Following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme system) or even in the portal blood, but most commonly it is the liver that is responsible for metabolism before the drug reaches the systemic circulation. In addition, the liver can excrete the drug into the bile. Any of these sites can contribute to this reduction in bioavailability, and the overall process is known as first-pass elimination. The effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio (ER) ... 

Decreased hepatic elimination of local anesthetics would also be anticipated in patients with reduced hepatic blood flow. 

For example, the hepatic elimination of lidocaine in patients anesthetized with volatile anesthetics (which reduce liver blood flow) is slower than in patients anesthetized with intravenous (or balanced) anesthetic techniques. 

Tizanidine o -Adrenoceptor agonist in the spinal cord Presynaptic and postsynaptic inhibition of reflex motor output Spasm due to multiple sclerosis, stroke, amyotrophic lateral sclerosis Renal and hepatic elimination t duration, 3-6 h Toxicities Weakness, sedation hypotension... 

For many drugs, at least part of the toxic effect may be different from the therapeutic action. For example, intoxication with drugs that have atropine-like effects (eg, tricyclic antidepressants) reduces sweating, making it more difficult to dissipate heat. In tricyclic antidepressant intoxication, there may also be increased muscular activity or seizures the body s production of heat is thus enhanced, and lethal hyperpyrexia may result. Overdoses of drugs that depress the cardiovascular system, eg, 13 blockers or calcium channel blockers, can profoundly alter not only cardiac function but all functions that are dependent on blood flow. These include renal and hepatic elimination of the toxin and any other drugs that may be given. 

SI -selective betablocker with a plasma half-life of three to seven hours and mainly hepatic elimination. 

Roberts MS, Donaldson JD, Rowland M. Models of hepatic elimination a comparison of stochastic models to describe residence time distributions and to predict the influence of drug distribution, enzyme heterogeneity, and systemic recycling on hepatic elimination. J Pharmacokinet Biopharm 1988 16 41-83. 

The effects of the P-gp inhibitor, GF120918, on the hepatobiliary disposition (biliary excretion) of doxorubicin were determined using a perfused rat liver system (270). Biliary excretion is the rate-limiting process for doxorubicin elimination. In the presence of GF120918, the biliary excretion of doxorubicin and its major metabolite, doxorubicinol, was decreased significantly without alterations in doxorubicin perfusate concentrations or doxombicin and doxorubicinol liver concentrations. In a similar study on the hepatic elimination of other P-gp substrates, including vincristine and daunorubicin, it was reported that canalicular P-gp plays a significant role in the biliary secretion of these compounds (428,429). 

For a drug that is eliminated exclusively by the liver and that is completely absorbed following oral administration, the intrinsic clearance can be related to the area under the plasma concentration-time curve (AUCp0) if the well-stirred model of hepatic elimination is assumed (81,82) ... 

Anissimov, Y., Bracken, A., and Roberts, M., Interconnected-tubes model of hepatic elimination Steady-state considerations, Journal of Theoretical Biology, Vol. 199, No. 4, 1999, pp. 435-447. 

Age Renal or hepatic elimination processes are often poorly developed in newborns, making neonates particularly vulnerable to the toxic effects of chloramphenicol (see p. 320) and sulfonamides (see p. 289). Young children should not be treated with tetracyclines (see p. 311) which affect bone growth, or fluoroquinolones (see p. 323), which interfere with cartilage growth. 

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