Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications
Caccia S
Istituto di Ricerche
Farmacologiche Mario Negri,
Milan, Italy.
Clin Pharmacokinet 1998 Apr; 34(4):281-302


Several chemically unrelated agents has been developed and introduced in the past decade, to supplement the earlier antidepressants. These include inhibitors of the reuptake of serotonin [the selective serotonin reuptake inhibitors (SSRI)] or noradrenaline (reboxetine) or both (milnacipran and venlafaxine), as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine. Like the earlier drugs, these newer antidepressants are almost totally biotransformed before excretion, except for milnacipran whose clearance appears to be due equally to both urinary excretion and metabolism. Sometimes--as in the case of moclobemide--up to 20 metabolites have been identified in body fluids. In some cases, however, only a few metabolites have been detected, and a substantial proportion of the dose remains unaccounted for (e.g. fluoxetine and fluvoxamine). Metabolism generally proceeds through sequential or parallel oxidative pathways. These may be affected to varying degrees by physiological and pathological factors and those mediated by cytochrome P450 (CYP) 2D6 and CYP2C19 through genetic polymorphism. Some are influenced by chirality (e.g. the dealkylation of citalopram and fluoxetine), although information on this aspect of disposition is still lacking for other drugs existing as racemates (e.g. mirtazapine and tianeptine) and milnacipran, which is probably a mixture of 4 stereoisomers. Others again are saturable within the therapeutic range of doses (e.g. some pathways of metabolism of fluoxetine, fluvoxamine, nefazodone, paroxetine and venlafaxine). This may explain the individual variability with all these drugs which, from the pharmacokinetic point of view, is the same as with tricyclic agents. Our knowledge of the isoenzymes involved in the various oxidation pathways and their relevance for potential drug interactions varies from a considerable amount for most of the SSRI and nefazodone, to minimal for reboxetine and tianeptine. This information is useful for predicting the pharmacokinetic interactions mediated through inhibition of specific isoenzymes. This would be better appreciated if the enzymatic mechanisms involved in the biotransformation of the metabolite(s), and their role in drug interactions, were also known. This information is still lacking for some drugs, although metabolites may exhibit in vitro inhibitory potencies of similar to (paroxetine and its M2 metabolite as inhibitors of CYP2D6) or even greater than that of the parent drug (norfluoxetine is more potent than fluoxetine as an inhibitor of CYP3A3/4, and in view of the longer half-life (t1/2) of the metabolite the potential for interactions may persist for weeks after discontinuation of the parent drug). While we do know something about the biological activity of the metabolites of some of these drugs, we know very little about others. With few exceptions this knowledge refers only to the major metabolite(s) and regards the main in vitro effects as exerted by the parent drug. However, in vitro potency and selectivity may not translate directly into in vivo, and either major or minor metabolites may have characteristic in vitro and in vivo properties. For example, unlike the parent drug some minor ring-opened metabolites of moclobemide have monoamine oxidase-B inhibitory activity in the rat, and the nefazodone metabolite m-chlorophenyl-piperazine shows activity on 5-HT2C receptors in rats and humans. Data on the brain-to-blood partition of metabolites compared with their parent drug are available only in a few cases. They are still not known for the main metabolites of fluvoxamine, milnacipran, mirtazapine, moclobemide, nefazodone, paroxetine, reboxetine and venlafaxine, despite the fact that total blood concentrations do not always reflect the metabolite: parent drug ratio in brain. Thus, in most cases, we do not really know what part hepatic metabolism plays in the overall effect of the administered parent drug.
Super-small doses
New antidepressants
Antidepressants: how fast?
Antidepressants: new indications
Subjective effects of antidepressants
Antidepressants and cytochrome P450
Antidepressants: ways to improve adherence

and further reading

Future Opioids
BLTC Research
Utopian Surgery?
The Abolitionist Project
The Hedonistic Imperative
The Reproductive Revolution
Critique of Huxley's Brave New World

The Good Drug Guide
The Good Drug Guide

The Responsible Parent's Guide
To Healthy Mood Boosters For All The Family