Clearance of toxins

Doucette et al. 2000). At lower doses neonates show delayed effects on eye opening and olfactory conditioned place preference (Doucette et al. 2003). The latter supports the high sensitivity of the mitral-granule cells to domoic acid as described earlier. Evidence indicates that the sensitivity of the neonates results from insufficient renal clearance of toxin, allowing increased bioavailability in the blood (Xi et al. 1997). Domoic acid has been detected in the blood of neonates, transmitted via milk from lactating mother rats previously exposed to domoic acid but at levels appearing to be well below symptomatic doses (Maucher and Ramsdell 2005). 

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

The splanchnic system drains venous blood from the GI tract to the liver. In portal hypertension there is increased resistance to drainage from the originating organ so collateral vessels (varices) develop in the esophagus, stomach, and rectum to compensate for the increased blood volume. Varices divert blood meant for hepatic circulation back to the systemic circulation this has the unintended deleterious effect of decreasing clearance of medications and potential toxins through loss of first-pass metabolism. Varices are weak superficial vessels, and any additional increase in pressure can cause these vessels to rupture and bleed.15... 

The only current treatment of EHEC infection is supportive, including fluid and electrolyte replacement, often in the form of ORT. Most illnesses resolve in 5 to 7 days. Patients should be monitored for the development of HUS. Antibiotics are currently contraindicated because they can induce the expression and release of toxin. Antimotility agents should be avoided because they may delay clearance of the pathogen and toxin. This, in turn, may increase the risk of systemic complications. 

A randomized open trial, performed in patients with C. difficile pseudomembranous colitis, compared rifaximin (200 mg 3 times daily) to vancomycin (500 mg 2 times daily) and found the two drugs similarly effective [141]. The clearance of bacterial toxins was, however, more rapid with vancomycin. Further large double-blind clinical studies are needed to better define the role of rifaximin in the treatment of C. difficile infection. 

No single toxin is responsible for all of the signs and symptoms of uremia observed in stage 4 or 5 CKD. Toxins accumulate as a result of increased secretion, decreased clearance secondary to reduced metabolism within the kidney, and/or decreased renal clearance of by-products of protein metabolism. 

Kidney failure not only decreases renal clearance of nicotine and cotinine, but also metabolic clearance of nicotine (Molander et al. 2000). Metabolic clearance of nicotine is reduced by 50% in subjects with severe renal impairment compared to healthy subjects. It is speculated that accumulation of uremic toxins may inhibit CYP2A6 activity or downregulate CYP2A6 expression in liver. Hepatic metabolism of several drugs is reduced in kidney failure, mainly via downregulation of CYP enzymes and/or inhibition of transporters (Nolin et al. 2003). 

During chronic alcohol consumption, MEOS activity is induced. As a result, chronic alcohol consumption results in significant increases not only in ethanol metabolism but also in the clearance of other drugs eliminated by the cytochrome P450s that constitute the MEOS system, and in the generation of the toxic byproducts of cytochrome P450 reactions (toxins, free radicals, H202). 

The gastrointestinal epithelium forms an extrinsic and an intrinsic barrier against diffusion of toxins and pathogens. The extrinsic barrier is characterized by secretion of mucus, which hinders colonization and accelerates clearance of pathogenic organisms. The importance of mucus as a barrier to drug absorption is discussed in Chapter 2 of this book. In addition, the intestinal immune... 

Poli and co-workers (Poli et al. 1990b Cattet and Geraci 1993) demonstrated that rats, when dosed intravenously, showed a rapid clearance of the labelled PbTx-3 toxin from the system. Examination of the excrement by thin layer chromatograply indicated the bioconversion of the toxin to more polar metabolites. This study corroborated the oral study, indicating that the main site of detoxification of the BTXs is the liver. 

These unmeasured anions are generated as the result of the consumption of HCOJ by endogenous organic acids such as lactic acid, acetoacetic acid, or / -hydroxybutyric acid or from the ingestion of toxins such as methanol or ethylene glycol. The degree of elevation in the SAG is dependent on the clearance of the anion, as well as the multiple factors that influence HCOJ concentrations. Thus the SAG is a relative rather than an absolute indication of the cause of metabolic acidosis. The SAG may also be elevated in the metabolic acidosis due to renal failure, as the result of the accumulation of various organic anions, phosphates, and sulfates. 

The reduced clearance of BSP in infective conditions may be an effect of pyrexia. However, the finding that a high proportion of patients with mild chronic ill-health secondary to chronic infection have reduced BSP disappearance rates (S38) and that direct warming of dogs to 42° has no effect (S40) suggests that toxins themselves may have an effect. 

It is believed that the lung infection results from impaired mucus clearance followed by colonization of bacteria in the mucus. The bacteria elaborate a number of toxins, polysaccharides, and enzymes including proteases, elastases, and exotoxin A, which may stimulate the production of additional mucus and further contribute to airway obstruction (Sam et al., 1980 Adler et al., 1983). Pseudomonas aeruginosa and Staphylococcus aureus are the most commonly found bacteria in the lungs of patients with CF, but Klebsiella, Esherichia coli, streptococci, and Haemophilus influenza can also be found. Of particular interest is the observation that mucoid strains of infectious bacteria, which are more pathogenic than nonmucoid strains, are most commonly found in patients with CF (Reynolds et al., 1975, 1976). The mucoid strains are also more resistant to phagocytosis by alveolar macrophages and are impermeable to antibiotics because of their mucoid coats. Thus treatment of pulmonary infections in patients with CF can be unusually difRcult. 

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