Excretion hepatic role

COLEMAN, R. and CHIPMAN, J.K. (1995) Factors governing biliary excretion. In Role of Gut Bacteria in Human Toxicology and Pharmacology, edited by M.J.Hill (London Taylor and Francis). KLAASSEN, C.D. (1984) Mechanisms of bile formation, hepatic uptake and biliary excretion. Pharmacol. Rev., 36, 1. 

Many of the phase 1 enzymes are located in hydrophobic membrane environments. In vertebrates, they are particularly associated with the endoplasmic reticulum of the liver, in keeping with their role in detoxication. Lipophilic xenobiotics are moved to the liver after absorption from the gut, notably in the hepatic portal system of mammals. Once absorbed into hepatocytes, they will diffuse, or be transported, to the hydrophobic endoplasmic reticulum. Within the endoplasmic reticulum, enzymes convert them to more polar metabolites, which tend to diffuse out of the membrane and into the cytosol. Either in the membrane, or more extensively in the cytosol, conjugases convert them into water-soluble conjugates that are ready for excretion. Phase 1 enzymes are located mainly in the endoplasmic reticulum, and phase 2 enzymes mainly in the cytosol. 

The liver plays an important role in determining the oral bioavailability of drags. Drag molecules absorbed into the portal vein are taken up by hepatocytes, and then metabolized and/or excreted into the bile. For hydrophilic drugs, transporters located on the sinusoidal membrane are responsible for the hepatic uptake [1, 2]. Biliary excretion of many drags is also mediated by the primary active transporters, referred to as ATP-binding cassette transmembrane (ABC) transporters, located on the bile canalicular membrane [1, 3-5], Recently, many molecular biological... 

The ability of the liver to act as a depot for vitamin Bi2 (B28, G13) enables us to use this vitamin as an index of proper hepatic function. Hepatic disorders lead to an increased Bi2-binding in the serum (J5, R3), suggesting that the blood assumes a greater role in the conservation of B12. We have reported that patients with liver disease excreted invariably less than 10 fig of Bi2> 8 hours after a 50-[ig intramuscular load dose of the vitamin. In contrast, normal subjects excreted 24-40 pg, i.e., 50-80% of the vitamin in the same test (B14). These results were correlated with various chemical determinations indicative of hepatic disorders (Bl). In Table 16 the clinical diagnosis and the various liver-... 

Hepatic metabolism and excretion in the bile play major roles in the elimination of both vinblastine and vincristine in humans (52) small amounts of vincristine and vinblastine, of the order of 10% of the administered dose, are excreted unchanged in urine. Renal clearance of vinblastine has been reported to be less than 10% of total serum clearance 53). Vinblastine has been reported to inhibit a polymorphic cytochrome P-450 system in human hepatic microsomes, but the concentrations required were much higher than those observed in clinical settings (54). 

What makes prediction of drug elimination complex are the multiple possible pathways involved which explain why there is no simple in vitro clearance assay which predicts in vivo clearance. Because oxidative metabolism plays a major role in drug elimination, microsomal clearance assays are often used as a first line screen with the assumption that if clearance is high in this in vitro assay it is likely to be high in vivo. This assumption is often, but not always true because, for example, plasma protein binding can limit the rate of in vivo metabolism. However, compounds which have a low clearance in hepatic microsomes can be cleared in vivo via other mechanisms (phase II metabolism, plasmatic errzymes). Occasionally, elimination is limited by hepatic blood flow, and other processes like biliary excretion are then involved. The conclusion is that the value of in vitro assays needs to be established for each chemical series before it can be used for compound optimization. 

Levine WG, Millburn P, Smith RL, et al. The role of the hepatic endoplasmic reticulum in the biliary excretion of foreign compounds by the rat. The effect of phenobarbitone and SKF 525-A diethylaminoethyl diphenylpropylacetate Biochem Pharmac 1970 19 235-244. 

Endogenous substances other than metallothionein may be involved in minimizing the effects of heavy metals and excreting them from the body. Hepatic (liver) glutathione, discussed as a phase II conjugating agent in Section 7.4, plays a role in the excretion of several metals in bile. These include the essential metals copper and zinc toxic cadmium, mercury(II), and lead(II) ions and organometallic methyl mercury. 

Zamek-GI i szczy nski MJ, Nezasa K, Tian X, et al. Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3-/- and Abcc4-/- mice. J Pharmacol Exp Ther 2006 319 1485-1491. 

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). 

Lohitnavy M, Lu Y, Lohitnavy O, Chubb LS, Hirono S, Yang RSH. 2008. A possible role of multidrug resistance-associated protein 2 (Mrp2) in hepatic excretion of PCB126, an environmental contaminant PBPK/PD modeling. Toxicol Sci 104 27-39. 

The already mentioned proteins OCTI and OCT3 transport small cationic substances, such as tetraalkyl ammonium compounds, polyamines such as spermine, monoamino-neurotransmitters, or N-methyl-nicotinamide across the basolateral plasma membrane [56]. OCTs play a key role in the distribution of cationic drugs and, therefore, drug interactions at the transporter level may become clinically relevant, as compounds with high affinity, such as prazosin or phenox-ybenzamine, may affect the excretion of other substrates. Certain liver diseases or obstructive cholestasis may result in alterations of hepatic clearance via these transporters. In rats, a 7-day bile duct ligation resulted in a marked downregulation of Octi and an increased hepatic accumulation of the Octi substrate tetraethylammonium [57]. 

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