|show drug details|
|1-Naphthalenamine, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-, hydrochloride, (1S-cis)-|
|1-Naphthalenamine, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-, hydrochloride,(1S-cis)-|
|Sertraline Hydrochloride (1S-cis)-Isomer|
|Sertraline hydrochloride (JAN/USAN)|
|Sertraline hydrochloride [USAN]|
|Ki: ||Kd:||Ic 50:||Ec50/Ic50:|
CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations.. C L Alfaro; Y W Lam; J Simpson; L Ereshefsky (2000) Journal of clinical pharmacology display abstract
The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DXAD) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DXAD ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DXAD ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; chi 2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DXAD ratios were found for sertraline and venlafaxine. Of note, the DM/DXAD for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DXAD were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DXAD correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation.
Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study.. R Scott Obach; Loretta M Cox; Larry M Tremaine (2005) Drug metabolism and disposition: the biological fate of chemicals display abstract
The oxidative and conjugative metabolism of sertraline was examined in vitro to identify the enzymes involved in the generation of N-desmethyl, deaminated, and N-carbamoyl-glucuronidated metabolites in humans. In human liver microsomes, sertraline was N-demethylated and deaminated by cytochrome P450 (P450) enzymes with overall K(m) values of 98 and 114 microM, respectively, but the intrinsic clearance for N-demethylation was approximately 20-fold greater than for deamination. Using P450 isoform-selective inhibitors and recombinant heterologously expressed enzymes, it was demonstrated that several P450 enzymes catalyzed sertraline N-demethylation, with CYP2B6 contributing the greatest extent, and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6. For deamination, data supported a role for CYP3A4 and CYP2C19. Purified human monoamine oxidases A and B also catalyzed sertraline deamination with comparable K(m) values (230-270 microM). Monoamine oxidase B catalyzed the reaction approximately 3-fold faster than did monoamine oxidase A. Sertraline N-carbamoyl glucuronidation was measured in human liver microsomes in bicarbonate buffer and under a CO2 atmosphere (K(m) = 50 microM) and was catalyzed at the fastest rate by recombinant human UGT2B7. The observation that multiple enzymes appear to be involved in sertraline metabolism suggests that there should be no single agent that could substantially alter the pharmacokinetics of sertraline, nor should there be any single drug-metabolizing enzyme genetic polymorphism (e.g., CYP2D6, CYP2C19, CYP2C9, UGT1A1) that could profoundly impact the pharmacokinetics of sertraline.
Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.. S E Ball; D Ahern; J Scatina; J Kao (1997) British journal of clinical pharmacology display abstract
AIMS: In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450 s was also studied (CYP3A4, CYP2D6, CYP1A2). METHODS: Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). RESULTS: Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (Ki values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 microM, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (Ki of 24.7 +/- 8.9 microM). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a Ki of 1.3 +/- 0.5 microM. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (Ki of 41.0 +/- 9.5 microM) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (Ki values of 3.9 +/- 1.7 and 1.7 +/- 0.9 microM, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. CONCLUSIONS: It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.