After the opioids are distributed throughout the body, there is termination of the drug's pharmacological activity and elimination of drug metabolites. To accomplish this, biotransformation of the opioid must take place. Biotransformation is a chemical process whereby drugs undergo structural change through a series of endogenous enzymatic reactions, which terminate their action and prepare the drug for elimination. For example, this mechanism transforms nonpolar molecules into more polar molecules, thus preventing reabsorption by the kidney in favor of excretion.
Biotransformation occurs primarily in the liver and consists of two phases. Phase I reactions may involve oxidation, hydrolysis, reduction, or hydration of the opioid to produce a more water-soluble and less active metabolite. The majority of metabolites produced during this phase are hydroxylated by the cytochrome P-450 enzyme system. Phase II involves a conjugation reaction which covalently attaches a small polar endogenous molecule, such as glucuronic acid, sulfate, or glycine, to a functional group on the opioid compound. This process yields a large molecular weight compound which is usually inactive and is more easily excreted.
While most opioid metabolites produced through Phase I and Phase II reactions are inactive and nontoxic, certain opioid metabolites are more toxic or potent than the parent compound. Meperidine is metabolized to normeperidine. This metabolite is potentially neurotoxic in patients placed on chronic therapy or who have poor renal function. Morphine is metabolized into two major metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), which rely on renal elimination. M3G possesses antinociceptive effects and M6G has analgesic properties which appear more potent than morphine (Christup 1997).
Parent opioid drugs or their metabolites are eliminated through many routes (renal, liver, sweat, tears, breast milk, and saliva). The kidneys are the primary elimination route, with almost 90% eliminated in the urine. Some opioid metabolites experience biotransformation in the liver, and their metabolites are excreted by the gastrointestinal tract after gaining entrance through bile.
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