Saturable metabolism

Dekant et al. 1986b Filser and Bolt 1979 Prout et al. 1985). Male mice can metabolize inhaled trichloroethylene to a greater extent than male rats (Stott et al. 1982). In this study, virtually 100% of the net trichloroethylene uptake by mice was metabolized at both 10- and 600-ppm exposure concentrations, and there was no evidence of metabolic saturation. In rats, however, 98% of the net trichloroethylene uptake from the 10-ppm exposure was metabolized, but only 79% was metabolized at the 600-ppm exposure level. This suggested an incremental approach to the saturation of metabolism in this exposure range in the rat. Rats exposed by inhalation to trichloroethylene concentrations of 50 or 500 ppm for 2 hours showed metabolic saturation at 500 ppm (Dallas et al. 1991). This was indicated by the fact that the trichloroethylene blood levels of the 500-ppm animals progressively increased over the 2-hour period, rather than approaching equilibrium after 25 minutes, as was the case at 50 ppm. 

In studies in rats and mink that used more than one dose, the area under the plasma-IMPA concentration time curves indicated that at high doses the principal pathway for the conversion of diisopropyl methylphosphonate to IMPA was saturated (Bucci et al. 1992). In rats, metabolism was saturated at an oral dose of 660 mg/kg, but not at 66 mg/kg in mink, an oral dose of 270 mg/kg caused metabolic saturation which did not occur at 27 mg/kg. 

Oxidation of saturated hydrocarbons. Although the initial oxidation step is chemically difficult, the tissues of our bodies are able to metabolize saturated hydrocarbons such as n-heptane slowly, and some microorganisms oxidize straight-chain hydrocarbons rapidly.30 31 Strains of Pseudomonas and of the yeast Candida have been used to convert petroleum into... 

As expected, based on very strong similarity with vinyl chloride in terms of kinetics and dynamics, vinyl bromide provided a truncated, but up to metabolic saturation, perfect dose response in terms of liver angiosarcoma in both male and female rats inhaling 0, 10, 50, 250, and 1250 ppm (44, 219, 1093, and 5875 mg m ) vinyl bromide. Increased tumor incidences were also observed in squamous cell carcinomas of the Zymbal gland and neoplastic nodules and hepatocellular carcinomas. 

Lorcainide (No. 15) is another local anesthetic-type antiarrtiythmic. Its pharmacokinetics are illustrative of the interpatient variabilities encountered. N-dealkylation to norlor-cainide is extensive on the first pass. The parent drug s plasma clearance tm is about 8 hours with the metabolite, which is active, it is 27 hours. Individual tm for the drug varied from 2.5 to over 15 hours. A single, small oral dose is only 4% bioavariable. However, with larger and repeated doses this can increase to over 20% (metabolic saturation). 

In order for this enzyme to work, a chemical known as S-adenosylmethionine (SAM) must be present in the liver. SAM is a derivative of the aunino acid methionine, which is essential to our health. There is only a certain amount of SAM in our liver that is available to combine with arsenic and render it nontoxic. If more au senic enters the liver than the amount of available SAM can handle, then excess non-metabolized au"-senic may accumulate in the liver and be distributed to other orgams, causing toxic effects. This is known ais metabolic saturation. As long as the aunount of arsenic (i.e., the dose) is below this saturation level, our liver can detoxify it and no toxic effects will result. It is only when the amount of arsenic overwhelms the metabolic pathway that toxic effects can develop. This illustration of a threshold below which toxic effects do not occur is a key concept in toxicology (see chapter 3 for a graphical illustration of the threshold concept). 

Based on this information, the dose level at which cancers first start to be seen from arsenic exposure is near the level at which the detoxification pathway is overwhelmed. Only epidemiological studies with arsenic concentrations in drinking water at or above 0.6 mg/L have reported incidence of skin cancers that increase with dose. The lowest estimated dose corresponding with positive studies of 0.011 mg/kg-day is slightly above the metabolic saturation threshold dose. This is solid evidence that arsenic does not act as a carcinogen in drinking water below this level. 

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