Entero-hepatic cycle

Figure 2.22. Outline of hepatic dmg metabolism and its role in drag elimination. I, II Phase I and phase II reactions. Some drags skip the phase I reaction and are directly conjugated. Metabolites may be either released into the blood stream and eliminated by the kidneys, or they may be secreted into the bile. In the latter case, deconjugation may occur in the intestine (largely due to bacterial enzymes), and the drags released may undergo entero-hepatic cycling .

Steinberg SE, Campbell CL, and Hillman RS (1979) Kinetics of the normal folate entero-hepatic cycle. Journal of Clinical Investigation 64, 83-8. 

FIGURE 31.2 Schematic representation of the main routes of drug absorption, distribution and ehmination (GIS = GI system). The red arrows represent die entero-hepatic cycle (see Section V.A.2.). 

K. Elomaa, S. Ranta, J. Tuominen, and P. Lahteenmaki, The possible role of entero-hepatic cycling on bioavailability of norethisterone and gestodene in women using combined oral contraceptives. Contraception 63 13-18 (2001). 

The liver, and also bacteria in the small and large intestine, can cause other structural modifications to bile acids as they undergo their entero-hepatic cycle. The formation of sulfate esters, already mentioned with respect to lithocholate in Section 4.2.1, is carried out primarily in the liver in man by a sulfotransferase (Lll). Other bile acids can also be sulfoconjugated to a small extent, mainly at the 3a-hydroxyl position. Bacteria, which have been isolated anaerobically from human feces, are known to possess bile acid sulfatase activity, which removes the 3a-sul te group of chenodeoxycholic and cholic acids (H24). The action of this bacterial enzyme probably explains why only trace amounts of sul ted bile acids, which are poorly absorbed in the intestine, are detected in the feces (12). Another type of bile acid conjugate, which has been identified in the urine of healthy subjects and patients with hepatobiliary disease, is the glucuronide (A7, S41). Both the liver and extrahepatic tissues, such as the kidney and small intestinal mucosa, are capable of glucuronidation of bile acids in man (M14). 

B. Pharmacokinetics Oral absorption is variable, especially for the older drugs, and may be impaired by foods and multivalent cations (calcium, iron, aluminum). Tetracyclines have a wide tissue distribution and cross the placental barrier. All of the tetracyclines undergo entero-hepatic cycling. Doxycycline is excreted mainly in feces the other drugs are eliminated primarily in the urine. The half-lives of doxycycline and minocycline are longer than those of other tetracyclines. 

Hendel, J. Brodthagen, H. Entero-hepatic cycling of methotrexate estimated by use of the D-isomer as a reference marker. Eur. J. Clin. Pharmacol. 1984, 26, 103 107. 

After entry in the blood stream the chylomicrons are hydrolyzed by the endothelial-bound lipoprotein lipase with apo C-I as a co-factor, allowing the delivery of free FAs to muscle and adipose tissue. The chylomicron remnants are rapidly taken up into the liver via especial receptor. ApoE is the moiety required for rapid hepatic removal. Its activity is inhibited by C apolipoproteins, especially apoC-I. The liver utilizes the exogenous fat and can release surplus lipids via VLDL into the blood. The VLDL is another substrate for lipoprotein lipase. The remaining VLDL remnants can either be taken up into the liver or are hydrolyzed to LDL. These last delivers cholesterol to all body cells via its receptor [136]. Moreover other type of lipoprotein denominated as high-density protein (HDL) is an important scavenger of surplus cholesterol transporting it from cell membranes to the liver, where it is degraded or converted into biliary salts, an then eliminated by the entero-hepatic cycle [137]. 

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