Paroxetine metabolism

Paroxetine metabolism at low concentrations is dependent on CYP2D6, which is almost saturated at these concentrations, Thus, there are non-linear pharmacokinetics and an increase in the half-life of paroxetine from 10 to 20 hours when the dose is increased from lOmg to 20mg, At higher concentrations, the metabolism is mainly by CYP3A4 isoenzymes, Paroxetine inhibits the activity of CYP2D6 in the lowest usually effective antidepressant dose,... 

Use of a hERG blocker in a patient also taking CYP3A4 inhibitors (e.g. antibacterial macrolides, azole antifungals, HIV protease inhibitors) or CYP2D6 inhibitors (quinidine, halofantrine, fluoxetine, paroxetine, thioridazine, terbinafine) the hERG blocker, if mostly metabolized by these CYP isoforms, may accumulate because... 

Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF. 1993. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44 349-355. 

Another factor which should be considered is the relative importance of the defective metabolic pathway in the overall metabolism of a drug. For example, paroxetine is metabolized by at least two pathways and the suboptimal activity of one enzyme has a relatively minor effect on the... 

P450 system Concomitant use of SSRIs with drugs metabolized by cytochrome P4502D6 may require lower doses than usually prescribed for either paroxetine or the other drug because paroxetine may significantly inhibit the activity of this isozyme. 

Bertelsen, K.M., Venkatakrishnan, K., Von Moltke, L.L., Obach, R.S. and Greenblatt, D.J. (2003) Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine comparison with fluoxetine and quinidine. Drug Metabolism and Disposition The Biolo cal Fate of Chemicals, 31, 289-293. 

Venkatakrishnan, K and Obach, R.S. (2005) In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metabolism and Disposition ... 

Venlafaxine, although its re-uptake inhibitory activity is not restricted to serotonin, is often classified as an SSRI because of its similar spectrum of adverse reactions. It has a short elimination half-life in contrast to the other serotonin re-uptake inhibitors. Fluoxetine, norfluoxetine and paroxetine are inhibitors of their own metabolism by CYP2D6 resulting in non-linear pharmacokinetic behavior. 

Brookes AJ, Lehvaslaiho H, Siegfried M, et al (2000) HGBASE a database of SNPs and other variations in and around human genes. Nucleic Acids Res 28 356-360 Brosen K, Naranjo CA (2001) Review of pharmacokinetic andpharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 11 275-283 Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF (1993) Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44 349-355... 

Nebert DW, Dieter MZ (2000) The evolution of drngmetabolism. Pharmacology 61 124-135 O Reilly RL, Bogue L, Singh SM (1994) Pharmacogenetic response to antidepressants in a multicase family with affective disorder. Biol Psychiatry 36 467-471 Ozdemir V, Tyndale RF, Reed K, et al (1999) Paroxetine steady-state plasma concentration in relation to CYP2D6 genotype in extensive metabolizers. J Clin Psychopharmacol 19 472-475... 

Alderman, J., Preskorn, S.H., Greenblatt, D.J., Harrison, W., Penen-berg, D., Allison, J., and Chung, M. (1997) Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. / Clin Psychopharmacol 17 284-291. 

SSRIs—fluvoxamine, fluoxetine, and paroxetine, more than sertraline and citalopram Inhibition of metabolism at CYP2D6 isoenzyme TCA toxicity due to up to 10-fold increase in TCA levels with coadministration Lower TCA dose Baumann, 1996... 

There are several antipsychotics that are substrates to CYP2D6 (von Bahr et ah, 1991 Jerling et ah, 1996 Ring et ah, 1996 (Fang and Gorrod, 1999 Flockhart and Oesterheld, 2000) (Table 26.3). Moreover, several antipsychotics may act as inhibitors of CYP2D6-mediated biotransformation. These include thioridazine, chlorpromazine, haloperidol, fluphenazine, and pimozide (Desta et ah, 1998 Shin et ah, 1999). Of particular salience is the fact that the serotonin selective reuptake inhibitors (SSRIs) fluoxetine and paroxetine are metabolized to a significant extent by this isoenzyme. 

Selective serotonin reuptake inhibitors. Currently available selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram. At present, expert opinion does not support the usefulness of these serotonergic compounds in the treatment of core ADHD symptoms (National Institute of Mental Health, 1996). Nevertheless, because of the high rates of comorbidity in ADHD, these compounds are frequently combined with effective anti-ADHD agents (see Combined Pharmacotherapy, below). Since many psychotropics are metabolized by the cytochrome P450 system (Nemeroff et ah, 1996), which in turn can be inhibited by the SSRIs, caution should be exercised when combining agents, such as the TCAs, with SSRIs. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

If one of these enzymes is inhibited by another drug, then the plasma levels of the concurrently administered drugs that rely on the enzyme for metabolism increase. For example, 2D6 is essential for the usual metabolism of tricyclic antidepressants (TCAs), which are substrates for this enzyme. Paroxetine inhibits 2D6. If a patient is taking a TCA and paroxetine is added, or vice versa, plasma TCA levels increase, which may result in increased TCA-related side... 

Because the hver metabolizes TCAs, drugs that inhibit or induce hepatic microsomal enzymes may alter plasma tricyclic levels. This is particularly true of CYP 2D6 inhibitors. In some individuals, this interaction may result in dangerously high levels of the TCA when a potent 2D6 inhibitor, such as paroxetine, is coadministered. 

Atomoxetine has not been shown to exert clinically significant inhibition of CYP 1A2, CYP 2C9, CYP 2D6, and CYP 3A isoenzymes (Sauer et al. 2004). However, paroxetine, a potent CYP 2D6 inhibitor, has been shown to increase plasma concentrations of atomoxetine and significantly increase the half-life of atomoxetine approximately 2.5-fold in extensive 2D6 metabolizers (Belle et al. 2002). Caution should be used when administering atomoxetine to patients taking albuterol or pressor agents because atomoxetine may potentiate the cardiovascular effects of albuterol or pressor agents. 

Many compounds have been evaluated for their effects on brain metabolism (London, 1993). A surprisingly limited number of common regional metabolic effects have been seen within drug classes. Antipsychot ics, especially the older typical antipsychotics, tend to be associated with changes in striatal metabolism consistent with the high density of D2 dopamine receptors in those brain structures (Cohen et al.. 1999). On the other hand, quite different patterns of metabolic effects have been seen following acute doses with paroxetine and fluoxetine, both of which are selective serotonin... 

Kennedy, SJU, Evans, K.R., Kruger, S., et al. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am. J. Psychiatry 158(h), 899-905, 2001. 

In contrast to anticonvulsants and alcohol, drugs such as bupropion, fluoxetine, fluvoxamine, nefazodone, quinidine, paroxetine, and some antipsychotics can inhibit specific CYP enzymes (7, 11, 36, 37, 41, 42, 43 and 44). Thus, TCAs, certain BZDs, bupropion, some steroids, and antipsychotics can all have their metabolism inhibited by drugs such as fluoxetine. For example, fluoxetine at 20 mg/day produces on average a 500% increase in the levels of coprescribed drugs which are principally dependent on CYP 2D6 for their clearance. That can lead to serious or even life-threatening toxicity if the drug has a narrow therapeutic index and the dose is not adjusted for the change in clearance caused by the coadministration of fluoxetine. 

SSRIs such as fluoxetine and paroxetine may inhibit the metabolism of antipsychotics, increasing their plasma levels and the chance for toxicity ( 517, 518). While antipsychotics may inhibit the metabolism of tricyclic antidepressants, or, in turn, have their metabolism inhibited by tricyclic antidepressants, the clinical relevance is uncertain. 

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