Pharmacokinetic aspects of MAOIs
All the commonly used MAOIs (monoamine oxidase inhibitors), exemplified by phenelzine, isocarboxazid and pargyline, are irreversible inhibitors of both forms of the enzyme, forming covalent bonds with the active sites on the enzyme surface. This is the reason why the effects of these drugs last for many days even though their blood concentrations are undetectable. This can result in an accumulation of the drugs following their long-term use as they can also inhibit their own metabolism. These drugs are metabolized in the liver largely by a process of acetylation. Because of the relevance of the genetic status of the patient to the rate of metabolism of many drugs that are acetylated (the half-life of a drug that is acetylated rapidly being shorter and therefore less likely to accumulate than one that is slowly acetylated), it was hypothesized that the acetylator status of patients being treated with the older type of MAOIs may be an important determinant of their therapeutic effects. Recent clinical studies, however, have failed to show that the acetylator status is an important determinant of the therapeutic action of the phenelzine type of drug.
Because the long duration of action of the older irreversible inhibitors of MAO could be responsible for drug and dietary interactions, different types of MAOIs have been synthesized which are reversible inhibitors of the enzyme. Such compounds have the advantage that their action on the enzyme can be terminated by the presence of the high concentration of a natural substrate. Thus, should a patient on such a reversible inhibitor inadvertently take a tyramine-rich food, the tyramine would overcome the inhibitory effect of the drug on the MAO in the gastrointestinal wall and be metabolized. The tyramine would not then be absorbed and lead to the chance of a hypertensive episode. However, the MAO activity in other tissues, including the brain, would remain inhibited by the drug so that the therapeutic benefits would be maintained. In addition to the advantage of being less likely to interact with dietary amines, reversible MAOIs have a shorter duration of action than the irreversible inhibitors. Brofaromine, for example, has a half-life of 12 hours in the brain, in contrast to several days in the case of the phenelzine type of MAOI. A further advantage of the reversible and selective inhibitors lies in their effects on brain amines. Initially an irreversible inhibitor such as clorgyline may show selectivity, but will lose this following chronic treatment due to its long duration of action and possible accumulation. Such an effect is less likely to occur with the reversible MAOIs, which will be metabolized more readily, will not accumulate and will therefore be less likely to inhibit the non-preferred isoenzyme. Several selective MAO-A type inhibitors have now been synthesized (e.g. brofaromine, cimoxatone, moclobemide and toloxatone) which have proven to be clinically effective antidepressants. There is evidence that some of these inhibitors, for example moclobemide, act as pro-drugs in that they form active metabolites in vivo which have a greater affinity for MAO-A than the parent compound. Of the selective and reversible MAO-B inhibitors, caroxazone and Ro 16-6491 are currently undergoing development.
All the commonly used MAOIs (monoamine oxidase inhibitors), exemplified by phenelzine, isocarboxazid and pargyline, are irreversible inhibitors of both forms of the enzyme, forming covalent bonds with the active sites on the enzyme surface. This is the reason why the effects of these drugs last for many days even though their blood concentrations are undetectable. This can result in an accumulation of the drugs following their long-term use as they can also inhibit their own metabolism. These drugs are metabolized in the liver largely by a process of acetylation. Because of the relevance of the genetic status of the patient to the rate of metabolism of many drugs that are acetylated (the half-life of a drug that is acetylated rapidly being shorter and therefore less likely to accumulate than one that is slowly acetylated), it was hypothesized that the acetylator status of patients being treated with the older type of MAOIs may be an important determinant of their therapeutic effects. Recent clinical studies, however, have failed to show that the acetylator status is an important determinant of the therapeutic action of the phenelzine type of drug.
Because the long duration of action of the older irreversible inhibitors of MAO could be responsible for drug and dietary interactions, different types of MAOIs have been synthesized which are reversible inhibitors of the enzyme. Such compounds have the advantage that their action on the enzyme can be terminated by the presence of the high concentration of a natural substrate. Thus, should a patient on such a reversible inhibitor inadvertently take a tyramine-rich food, the tyramine would overcome the inhibitory effect of the drug on the MAO in the gastrointestinal wall and be metabolized. The tyramine would not then be absorbed and lead to the chance of a hypertensive episode. However, the MAO activity in other tissues, including the brain, would remain inhibited by the drug so that the therapeutic benefits would be maintained. In addition to the advantage of being less likely to interact with dietary amines, reversible MAOIs have a shorter duration of action than the irreversible inhibitors. Brofaromine, for example, has a half-life of 12 hours in the brain, in contrast to several days in the case of the phenelzine type of MAOI. A further advantage of the reversible and selective inhibitors lies in their effects on brain amines. Initially an irreversible inhibitor such as clorgyline may show selectivity, but will lose this following chronic treatment due to its long duration of action and possible accumulation. Such an effect is less likely to occur with the reversible MAOIs, which will be metabolized more readily, will not accumulate and will therefore be less likely to inhibit the non-preferred isoenzyme. Several selective MAO-A type inhibitors have now been synthesized (e.g. brofaromine, cimoxatone, moclobemide and toloxatone) which have proven to be clinically effective antidepressants. There is evidence that some of these inhibitors, for example moclobemide, act as pro-drugs in that they form active metabolites in vivo which have a greater affinity for MAO-A than the parent compound. Of the selective and reversible MAO-B inhibitors, caroxazone and Ro 16-6491 are currently undergoing development.
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