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Influence of medication on typical exercise response
Published in R. C. Richard Davison, Paul M. Smith, James Hopker, Michael J. Price, Florentina Hettinga, Garry Tew, Lindsay Bottoms, Sport and Exercise Physiology Testing Guidelines: Volume II – Exercise and Clinical Testing, 2022
Enterohepatic circulation refers to a process whereby medications absorbed in the small intestine become bound to bile salts in the liver and are stored in the gall bladder, before they are excreted back into the small intestine when they can be absorbed again (Figure 1.5.2). At first, this concept may seem strange, but many lipophilic molecules undergo this process. It also means that we can prescribe smaller doses of a drug since this pathway can recycle it. Important for us in this respect is that steroid hormones, derived from cholesterol and other lipophilic medications (e.g., Paracetamol, Aspirin) use this pathway. Exercise speeds up the excretion of bile salts, due to the increased gastric motility (Molina-Molina et al., 2018), but the concurrent reduction in splanchnic blood flow and increase in gastric motility means that less of these types of molecules are reabsorbed.
Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
A unique feature of the GSH and GSH S-conjugate degradation pathway is that the two enzymes, γ-glutamyltransferase and cysteinylglycine dipeptidase, that catalyze the reactions whereby cysteine and cysteine S-conjugates are formed, are membrane bound with their active sites facing the exterior fluid surrounding the cell. GSH S-conjugates that are transported into bile are delivered to the small-intestinal lumen as the intact conjugates or they are acted on by γ-glutamyltransferase and cysteinylglycine dipeptidase in the biliary epithelium to yield the corresponding cysteine S-conjugates (Ballatori et al., 1988; Lash et al., 1988; Stevens and Jones, 1989). Both the intestinal epithelium (Grafstrom et al., 1979) and the intestinal microflora (Larsen, 1985) can metabolize both the GSH and the cysteine S-conjugates to other sulfur-containing metabolites (see below). These products are either excreted in the feces or undergo enterohepatic circulation via the portal vein and are thereby returned to the liver for additional metabolism or for translocation to the kidneys (Figure 6). The predominant metabolites that are delivered to the kidneys are the N-acetylcysteine S-conjugates (i.e., mercapturates) and the cysteine S-conjugates (Stevens and Jones, 1989), although GSH S-conjugates may also be delivered, depending on the route of parent compound administration and the metabolic or nutritional state of the animal (Lash et al, 1988).
Effects of Antithrombotic and Results of Drug Screening
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
Dipyridamole has a relatively short-lived effect after both oral and parenteral administration. The high variability of its effectiveness, attaining differences of one order of magnitude, is caused mainly by its low solubility with subsequently difficult absorption in the gastrointestinal tract. When in blood, the drug is almost completely bound to plasmatic proteins and is eliminated mainly by glucuronidation in the liver. The enterohepatic circulation contributes to the variability of effects. A small portion is excreted by the kidney.
Safety considerations for the management of cholestatic itch
Published in Expert Opinion on Drug Safety, 2021
The currently available therapies target four different pathophysiologic mechanisms as illustrated in Figure 1 and Table 1. Elimination of pruritogens from the enterohepatic circulation.Altered metabolism of pruritogens by enzymatic induction.Modulation of neural pathway of pruritus by regulating central and peripheral endogenous opioid, serotonin or nonspecific nociceptive receptors.Altered itch perception.
Insights from pharmacokinetic models of host-microbiome drug metabolism
Published in Gut Microbes, 2020
Maria Zimmermann-Kogadeeva, Michael Zimmermann, Andrew L. Goodman
To this end, we simulated the model for each of the 10,000 random parameter sets with two (low and high) values of either biliary secretion coefficient kEH, or bacterial glucuronidase activity kdglB, and calculated the systemic exposure differences of both drug and drug metabolites between conditions. Enterohepatic circulation most strongly affects drug exposure under conditions that lead to an intact drug in the intestine that can be reabsorbed into circulation (Figure 4b). This is achieved if the drug is readily absorbed from the large intestine, if bacterial glucuronidase activity is high, or if bacterial drug metabolism activity is low. Under the same conditions, systemic metabolite exposure is determined by microbial glucuronidase and host glucuronyl-transferase activity. The propagation coefficient in the large intestine (kp3) also affected systemic metabolite exposure, underlining the importance of intestinal motility in determining host and microbiome contributions to metabolism of enterohepatically cycled drugs. Bacterial glucuronidase activity affected systemic drug levels under the same conditions as enterohepatic circulation, as it directly depends on the latter (Figure 4c).
Role of the microbiota in circadian rhythms of the host
Published in Chronobiology International, 2020
The enterohepatic circulation, in which the liver secretes bile into the intestine and reabsorbs them in the distal ileum, follows a daily rhythm (Govindarajan et al. 2016; Parkar et al. 2019). However, some of these liver-derived conjugated bile acids flow into the colon and are deconjugated by gut bacteria possessing the enzyme bile salt hydrolase. The emerging unconjugated bile acids are subject to further microbial modifications via bile acid-inducible enzymes, which create secondary bile acids like deoxycholic acid (DCA) and lithocholic acid (Govindarajan et al. 2016; Parkar et al. 2019). If mice are given the microbiota-derived unconjugated bile acids DCA and chenodeoxycholic acid orally, the expression of clock genes and clock-controlled genes is altered in the ileum, colon, and liver (Govindarajan et al. 2016). The effects of unconjugated bile acids on circadian clock genes are not achieved by the equimolar administration of conjugated bile acids. Only the gut bacteria can produce unconjugated and secondary bile acids and, therefore, indirectly influence host circadian rhythms (Govindarajan et al. 2016). Lastly, orally administered bile acids alter the microbial composition and are also subject to the enterohepatic circulation of the host (Govindarajan et al. 2016).