EXHIBIT H Toxic Metabolites

The metabolite produced from a drug or some other exogenous substance is often pharmacologically active. Such substances are referred to as active metabolites. In some cases, active metabolites are responsible for toxic effects which exceed that of the parent substance. Methanol, ethylene glycol, and DDE are examples of active toxic metabolites. Methanol (wood alcohol) can be ingested accidentally or intentionally. Methanol is metabolized similarly to ethanol, via a two-step oxidation to an aldehyde (formaldehyde) that is converted to an add (formic add). The acid causes toxic effects such as acidosis and Impaired cell respiration, while the penetration of methanol into the vitreous humor can lead to blurred vision emd blindness. 

Ethylene glycol (antifreeze) has a sweet taste that makes it attractive to animals and children, resulting in frequent acddental poisonings. Although the metabolic process is more complicated, active toxic metabolites of the corresponding aldehyde and adds are produced. Particularly insidious is the formation of crystals of calcium oxalate (Ksp (hydrate), 10 ), which may be detected as crystals in the urine. 

The final step is excretion of the drug and metabolites from the body. Water-soluble materials are excreted in the urine and in sweat. If a metabolite is a gas, such as CO2, or has appreciable vapor pressure, as does ethanol, the metabolite can be eliminated by exhalation. Excretion in feces, tears, and any other body fluid is also possible. 

Estimates of time since the administration of a drug are made easier when there is more than one substance present in the blood, urine, or other tissue sample. Recall that metabolism produces metabolites that are also subject to elimination. The concentration of the drug in blood or another compartment will decrease as metabolism progresses and the concentration of the metabolite increases. If the metabolite is subject to further biological transformatitms, it, too. 

Half-life Range, Blood (hours) Detectable in Urine (days) 

---