Drugs online research references
J Clin Psychopharmacol. 1997 Apr;17(2):102-6.
CYP2D6 inhibition in patients treated with sertraline.
Sproule BA, Otton SV, Cheung SW, Zhong XH, Romach MK, Sellers EM.
Addiction Research Foundation, Toronto, Ontario, Canada.
Sertraline, a selective serotonin reuptake inhibitor used to treat depression, inhibits CYP2D6 in vitro (Ki = 1.2 microM) less potently than fluoxetine (Ki = 0.15 microM). To determine the extent and time course of CYP2D6 inhibition in patients, six males (mean age: 40 years, range: 29-64 years), who were starting treatment for depression with sertraline, were phenotyped on five occasions (once before treatment and approximately 3, 7, 14, and 21 days later). Phenotype status was determined using oral dextromethorphan (30 mg) by calculating the urinary ratio of O-demethylated metabolites to parent drug (i.e., log ODMR). CYP2D6 genotype was determined by leukocyte DNA analysis using polymerase chain reaction amplification. Compliance was confirmed by sertraline plasma levels. Daily sertraline dosages ranged from 50 to 150 mg. Genotype results indicated all subjects were extensive metabolizers (four homozygous wild type [wt], two heterozygous wt/B mutation). Phenotype results showed that CYP2D6 inhibition in patients treated with sertraline appeared to be related to baseline CYP2D6 activity and sertraline dosage. Some patients with high CYP2D6 activity can demonstrate inhibition with sertraline dosages as low as 50 mg.
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J Auton Pharmacol. 1999 Dec;19(6):365-9.
Sertraline inhibits the contractile responses to noradrenaline, KCl and electrical field stimulation of rat isolated vas deferens.
Kalyoncu NI, Ozyavuz R, Karaoglu S.
Karadeniz Technical University Medical School, Department of Pharmacology, Trabzon, Turkey.
1. The aim of this study was to investigate the effect of sertraline, a selective serotonin re-uptake inhibitor, on contractile responses to noradrenaline (NA), KCl, serotonin (5-HT) and electrical field stimulation of rat isolated vas deferens. 2. Pre-treatment with 10(-4) M sertraline showed inhibitory effects on responses to NA, KCl, 5-HT and electrical field stimulation, while pre-treatment with 10(-6) and 10(-5) M sertraline caused potentiation of responses to NA (10(-7) and 10(-6) M). 3. A voltage-dependent calcium channel activator, Bay K 8644, restored the inhibited responses when sertraline was washed out of the organ bath, although restoration could not be seen when sertraline was not removed. 4. The inhibition of the contractile responses by sertraline pre-treatment may be via a mechanism through calcium channels which is additional to the selective serotonin re-uptake inhibitory effect of sertraline.
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Drug Metab Dispos. 2000 Oct;28(10):1176-83.
CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants.
Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, Greenblatt DJ.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, and the Division of Clinical Pharmacology, New England Medical Center, Boston, Massachusetts, USA.
The in vitro biotransformation of bupropion to hydroxybupropion was studied in human liver microsomes and microsomes containing heterologously expressed human cytochromes P450 (CYP). The mean (+/-S.E.) K(m) in four human liver microsomes was 89 (+/-14) microM. In microsomes containing cDNA-expressed CYPs, hydroxybupropion formation was mediated only by CYP2B6 at 50 microM bupropion (K(m) 85 microM). A CYP2B6 inhibitory antibody produced more than 95% inhibition of bupropion hydroxylation in four human livers. Bupropion hydroxylation activity at 250 microM was highly correlated with S-mephenytoin N-demethylation activity (yielding nirvanol), another CYP2B6-mediated reaction, in a panel of 32 human livers (r = 0.94). The CYP2B6 content of 12 human livers highly correlated with bupropion hydroxylation activity (r = 0.96). Thus bupropion hydroxylation is mediated almost exclusively by CYP2B6 and can serve as an index reaction reflecting activity of this isoform. IC(50) values for inhibition of a CYP2D6 index reaction (dextromethorphan O-demethylation) by bupropion and hydroxybupropion were 58 and 74 microM, respectively. This suggests a low inhibitory potency versus CYP2D6, the clinical importance of which is not established. Since bupropion is frequently coadministered with other antidepressants, IC(50) values (microM) for inhibition of bupropion hydroxylation were determined as follows: paroxetine (1.6), fluvoxamine (6.1), sertraline (3.2), desmethylsertraline (19.9), fluoxetine (59.5), norfluoxetine (4.2), and nefazodone (25.4). Bupropion hydroxylation was only weakly inhibited by venlafaxine, O-desmethylvenlafaxine, citalopram, and desmethylcitalopram. The inhibition of bupropion hydroxylation in vitro by a number of newer antidepressants suggests the potential for clinical drug interactions.
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