Hepatic transport system

Boyer JL, Graf J, and Meier PJ. Hepatic transport systems regulating pH, cell volume, and bile secretion. Ann Rev Physiol 1992 54 415-438. 

Table 9,3 Hepatic transport systems and their localization in hepatocyte membranes.

Furthermore, in the apical tubular membrane, the transport proteins Oatpl, Oatkl, and Oatk2, the Na +/phosphate cotransporter NPTl, and the primary active export proteins P-glycoprotein, Mrp2, Mrp4, and Berp have been identified [12, 95, 97-100]. Substrate requirements of the ABC transporters have already been discussed in the context of hepatic transport systems. Renal ABC transporters are well... 

Plasma bile acids (total bile acids, TBAs) have been recommended as an alternative measurement to plasma bilirubin because TBAs can indicate biliary functionality in terms of the response to food intake. TBA values are dependent upon a number of factors, including stomach emptying gall bladder contraction, where it exists intestinal motility intestinal absorption hepatic uptake and hepatic excretion. The enterohepatic circulation amplifies deficiencies in the hepatic transport system this results in reduced secretion of bile acids into the bile. Studies with dogs have shown that timed postprandial measurements have greater diagnostic value than fasting or random samples (Center et al. 1991 Jensen and Poulsen 1992), but the collection of timed postprandial samples is more difficult. 

Ferenci, P., G. Zollner, and M. Trauner. 2002. Hepatic transport systems. Journal of Gastroenterology and Hepatology 17 (Suppl) S106-S113. 

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. 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

Bile is produced continuously by the liver bile salts are secreted by the hepatocytes and the water, sodium bicarbonate, and other inorganic salts are added by the cells of the bile ducts within the liver. The bile is then transported by way of the common bile duct to the duodenum. Bile facilitates fat digestion and absorption throughout the length of the small intestine. In the terminal region of the ileum, the final segment of the small intestine, the bile salts are actively reabsorbed into the blood, returned to the liver by way of the hepatic portal system, and resecreted into the bile. This recycling of the bile salts from the small intestine back to the liver is referred to as enterohepatic circulation. 

Wieland, T., et al. Identity of hepatic membrane transport systems for bile salts, phalloidin, and antamanide by photoaffinity labeling. Proc. Natl. Acad. Sci. U. S. A. 1984, 81, 5232-5236. 

Drug molecules that have traversed the physieal and enzymatic barriers of the colonic mucosa may enter the blood-eapillary bed or the lymphatic sinuses. Intact drug that reaches the venous capillaries from the submucosa is transported to the liver via the hepatic-portal system where they may undergo significant metabolism. On the other hand, uptake into the lymphatie sinuses of the colon results in direct delivery into the systemic circulation that causes less metabolic breakdown of the absorbed drug [3]. 

Fig. 5.3 Structures of two combined TxSI/TxRAs subject to high hepatic extraction by sinusoidal transport systems.

Compound A appears mainly as unchanged drug in the bile whereas compound B appears partly as metabolites. Administration of ketoconazole, a potent cytochrome P450 inhibitor, to the preparation dramatically decreases the metabolism of B and the compound appears mainly as unchanged material in the bile. Despite the inhibition of metabolism, hepatic extraction remains high (0.9). This indicates that clearance is dependent on hepatic uptake, via a transporter system, for removal of the compounds from the circulation. Metabolism of compound B is a process that occurs subsequent to this rate-determining step and does not influence overall clearance. This model for the various processes involved in the clearance of these compounds is illustrated in Figure 5.4. 

K.L. Brouwer. 2005. Multiple transport systems mediate the hepatic uptake and biliary excretion of the metabolically stable opioid peptide [D-penicillami-ne2,5]enkephalin. Drug Metab. Dispos. 33 287-293. 

The mechanism in hepatic cellular metabolism involves an electron transport system that functions for many drugs and chemical substances. These reactions include O-demethylation, N-demethyla-tion, hydroxylation, nitro reduction and other classical biotransformations. The electron transport system contains the heme protein, cytochrome P-450 that is reduced by NADPH via a flavoprotein, cytochrome P-450 reductase. For oxidative metabolic reactions, cytochrome P-450, in its reduced state (Fe 2), incorporates one atom of oxygen into the drug substrate and another into water. Many metabolic reductive reactions also utilize this system. In addition, there is a lipid component, phosphatidylcholine, which is associated with the electron transport and is an obligatory requirement for... 

Hepatic mitochondria isolated from copper-deficient animals were found to be deficient in the cytochrome oxidase activity which correlated well with hem synthesis (57). Failure to synthesize hem from ferric iron and protoporphyrin could be enhanced by succinate or inhibited by cyanide, which suggests that the reduction from ferric to ferrous requires an intact electron transport system in order for hem synthesis to go into completion. 

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