Drug metabolism
Metabolism is an integral part of drug elimination. As well as facilitating excretion of a drug, it may also affect the pharmacological response of a drug by altering its potency and/or duration of action. With few exceptions, the metabolites of drugs are more polar (and water soluble) than the parent drug and are therefore more likely to be excreted from the body. Metabolites may be pharmacologically inactive (e.g. salbutamol sulfate) or they may be active. This is the case with many drugs of toxicological interest. For example, glucuronidation of morphine on the 6-hydroxyl moiety yields an opioid with more activity than morphine itself. The hydroxylation of THC to the 11-hydroxy form yields an active cannabinoid. Hydroxylation and demethylation of the benzodiazepine diazepam gives the metabolites temazepam and oxazepam, both of which are also available as drugs. Similarly, amitriptyline, a tricyclic anti-depressant, is demethylated to yield another antidepressant, nortriptyline. Heroin is deacetylated to 6-acetylmorphine and morphine, both potent opioids.
Active metabolites may also have different modes of action and different potencies; thus dealkylation of the antidepressant drug iproni azid gives the tuberculostatic drug isoniazid, while the anticonvulsants primidone and methylphenobarbital are both metabolised to phenobarbital, another anticonvulsant with a much longer duration of action. Clearly, the formation of active metabolites changes the profile of drug action. Pathways of drug metabolism can be divided into two types: Phase I and Phase II.
• Phase I reactions include oxidation, hydroxyl ation, N- and O-dealkylation and sulfoxide formation as well as reduction and hydrolysis reactions.
• Phase II processes involve conjugation reactions, such as with glucuronic acid, as well as acetylation, methylation and conjugation with amino acids and sulfate. Phase II reactions remove or mask functional groups (e.g. amino, carboxyl, hydroxyl, sulfhydryl, etc.) on the drug or Phase I metabolite by the addition of an endogenous substrate. Examples of Phase 1 reactions such as oxidation, Many drugs undergo a combination of Phase I and Phase II reactions. The major Phase II reaction is conjugation of glucuronic acid with the phenolic or alcoholic hydroxyl groups that are common products of Phase I reactions. Thus, chlorpromazine gives rise to at least 20 metabolites by its three major routes of metabolism (hydroxylation, N-demethylation and sulfoxidation). Fortunately, such complicated patterns of metabolism are not a major problem to the analyst since at most only one or two key metabolites are usually targeted during a toxicological analysis, these typically being major metabolites or those which are particularly diagnostic.
As noted previously, the liver is a major site of metabolism. Many of the critical pathways are catalysed by microsomal membrane-bound enzymes in the hepatocytes (parenchymal cells of the liver). For example, the cytochrome P450 mixed-function oxidase system (which catalyses oxidations) and glucuronyl transferase (the enzyme responsible for conjugation with glucuronic acid) are both located on microsomal membranes. Metabolism can occur in tissues other than the liver. The major additional sites are the gastrointestinal tract, kidneys and lungs. Their contribution clearly depends on the route of administration. For example, many metabolic reactions occur in the gastrointestinal tract before an orally administered drug is absorbed, carried out by enzymes in the mucosal lining or by microflora. Most of these reactions involve reduction and hydrolysis because of the anaerobic environment. Plasma esterases cause exten sive hydrolysis of drugs such as heroin, cocaine and procaine. In postmortem cases, anaerobic bioconversion occurs by endogenous enzymes active in such situations or by invading gastrointestinal bacteria. The nitro benzodiazepines nitrazepam, clonazepam and flunitrazepam are subject to reduction to their 7-amino metabolites. Using drugs principally of forensic interest, a number of examples are given below to illustrate the variety of metabolic routes that can be followed in humans and the effects that these might have on disposition and pharmacological activity. The examples given are not intended to be exhaustive with regard to either the pathways or the drugs covered. All the major oxidative mechanisms can be illustrated by considering the metabolism of the benzodiazepines, amfetamines, antidepressants and opioids.
