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Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes.. A Hemeryck; C De Vriendt; F M Belpaire (1999) European journal of clinical pharmacology display abstract
OBJECTIVE: To investigate the in vitro potential of selective serotonin reuptake inhibitors (SSRIs) to inhibit two CYP2C9-catalysed reactions, tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. METHODS: The formation of 4-hydroxytolbutamide from tolbutamide and that of 7-hydroxywarfarin from (S)-warfarin as a function of different concentrations of SSRIs and some of their metabolites was studied in microsomes from three human livers. RESULTS: Both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation followed one enzyme Michaelis-Menten kinetics. Kinetic analysis of 4-hydroxytolbutamide formation yielded a mean apparent Michaelis-Menten constant (Km) of 133 microM and a mean apparent maximal velocity (Vmax) of 248 pmol x min(-1) x mg(-1); formation of 7-hydroxywarfarin yielded a mean Km of 3.7 microM and a mean Vmax of 10.5 pmol x min(-1) x mg(-1). Amongst the SSRIs and some of their metabolites tested, only fluvoxamine markedly inhibited both reactions. The average computed inhibition constant (Ki) values and ranges of fluvoxamine when tolbutamide and (S)-warfarin were used as substrate, were 13.3 (6.4-17.3) microM and 13.0 (8.4-18.7) microM, respectively. The average Ki value of fluoxetine for (S)-warfarin 7-hydroxylation was 87.0 (57.0-125) microM. CONCLUSION: Amongst the SSRIs tested, fluvoxamine was shown to be the most potent inhibitor of both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Fluoxetine, norfluoxetine, paroxetine, sertraline, desmethylsertraline, citalopram, desmethylcitalopram had little or no effect on CYP2C9 activity in vitro. This is consistent with in vivo data indicating that amongst the SSRIs, fluvoxamine has the greatest potential for inhibiting CYP2C9-mediated drug metabolism.
Effect of fluvoxamine on the pharmacokinetics of quinidine.. P Damkier; L L Hansen; K BrÝsen (1999) European journal of clinical pharmacology display abstract
OBJECTIVE: To investigate the possible involvement of cytochromes CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine. METHODS: This was an open study of six healthy young male volunteers. The pharmacokinetics of a 200-mg single oral dose of quinidine were studied before and during daily treatment with 100 mg fluvoxamine. Biomarkers of other isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. RESULTS: The results showed a statistically significant median reduction of 2944% in the quinidine total apparent oral clearance, partial clearances by 3-hydroxylation and N-oxidation and residual clearance during fluvoxamine treatment. Renal clearance was unaffected by fluvoxamine. CONCLUSIONS: The effect of fluvoxamine on the formation clearances of 3-hydroxyquinidine and quinidine-N-oxide most likely reflects inhibition of cytochrome P4503A4 by fluvoxamine at clinically relevant doses. The results of this study do not rule out a possible involvement of CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine.
Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide.. H Madsen; T P Enggaard; L L Hansen; N A Klitgaard; K BrÝsen (2001) Clinical pharmacology and therapeutics display abstract
OBJECTIVE: Our objective was to examine the interaction between fluvoxamine and tolbutamide to confirm that fluvoxamine inhibits CYP2C9. METHODS: The study was carried out as an open, randomized, crossover design with 14 healthy participants. In period A, all volunteers took 500 mg of tolbutamide orally. In period B, the volunteers were randomly assigned to one of two groups. Each group took either 150 mg or 75 mg of fluvoxamine a day for 5 days (day -3 to day 2). The groups then took 500 mg of tolbutamide as a single dose (day 0). In both periods, blood and urine were sampled at regular intervals. Plasma was analyzed for tolbutamide, and urine was analyzed for tolbutamide and its two metabolites, 4-hydroxytolbutamide and carboxytolbutamide by means of HPLC. RESULTS: During treatment with fluvoxamine, there was a statistically significant decrease in the median of the total clearance of tolbutamide, from 845 mL/h to 688 mL/h, among the volunteers who received 75 mg/d. There was a reduction that reached borderline statistical significance in the group that received 150 mg/d of tolbutamide. The clearance by means of 4-hydroxytolbutamide and carboxytolbutamide was significantly reduced in both groups (ie, from 901 mL/h to 318 mL/h in the group that received 150 mg of tolbutamide per day and from 723 mL/h to 457 mL/h in the group that received 75 mg of tolbutamide per day). Thus there was a tendency toward a more pronounced inhibition of the 4-hydroxylation during treatment with 150 mg/d of fluvoxamine compared with 75 mg/d, but the difference was not statistically significant. CONCLUSION: Fluvoxamine is a moderate inhibitor of CYP2C9 in vivo.
Effects of fluvoxamine on lansoprazole pharmacokinetics in relation to CYP2C19 genotypes.. Norio Yasui-Furukori; Masato Saito; Tsukasa Uno; Takenori Takahata; Kazunobu Sugawara; Tomonori Tateishi (2004) Journal of clinical pharmacology display abstract
Lansoprazole is a substrate of CYP2C19 and CYP3A4. The aim of this study was to compare the inhibitory effects of fluvoxamine, an inhibitor of CYP2C19, on the metabolism of lansoprazole between CYP2C19 genotypes. Eighteen volunteers--of whom 6 were homozygous extensive metabolizers (EMs), 6 were heterozygous EMs, and 6 were poor metabolizers (PMs) for CYP2C19--received three 6-day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 60-mg dose of lansoprazole on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were monitored up to 24 hours after the dosing. During placebo administration, there was a significant difference in the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) of lansoprazole between CYP2C19 genotypes. Fluvoxamine treatment increased AUC(0-infinity) of lansoprazole by 3.8-fold (P < .01) in homozygous EMs and by 2.5-fold (P < .05) in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in the fluvoxamine-mediated percentage increase in the AUC(0-infinity) of lansoprazole between CYP2C19 genotypes. The present study indicates that there are significant drug interactions between lansoprazole and fluvoxamine in EMs. CYP2C19 is predominantly involved in lansoprazole metabolism in EMs.
Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.. Oliver von Richter; Gezim Lahu; Andreas Huennemeyer; Rolf Herzog; Karl Zech; Robert Hermann (2007) Clinical pharmacokinetics display abstract
OBJECTIVE: To investigate the effects of steady-state dosing of fluvoxamine, an inhibitor of cytochrome P450 (CYP) 1A2 and CYP2C19, on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor and its pharmacodynamically active metabolite roflumilast N-oxide. METHODS: In an open-label, non-randomised, one-sequence, two-period, two-treatment crossover study, 14 healthy subjects received a single oral dose of roflumilast 500 microg on study day 1. After a 6-day washout period, repeated doses of fluvoxamine 50 mg once daily were given from days 8 to 21. On day 15, roflumilast 500 microg and fluvoxamine 50 mg were taken concomitantly. Percentage ratios of test/reference (reference: roflumilast alone; test: roflumilast plus steady-state fluvoxamine) of geometric means and their 90% confidence intervals for area under the plasma concentration-time curve, maximum plasma concentration (roflumilast and roflumilast N-oxide) and plasma clearance of roflumilast were calculated. RESULTS: Upon co-administration with steady-state fluvoxamine, the exposure to roflumilast as well as roflumilast N-oxide increased by a factor of 2.6 and 1.5, respectively. Roflumilast plasma clearance decreased by a factor of 2.6, from 9.06 L/h (reference) to 3.53 L/h (test). The combined effect of fluvoxamine co-administration on roflumilast and roflumilast N-oxide exposures resulted in a moderate (i.e. 59%) increase in total PDE4 inhibitory activity. CONCLUSION: Co-administration of roflumilast and fluvoxamine affects the disposition of roflumilast and its active metabolite roflumilast N-oxide most likely via a potent dual pathway inhibition of CYP1A2 and CYP2C19 by fluvoxamine. The exposure increases observed for roflumilast N-oxide are suggested to be attributable to CYP2C19 co-inhibition by fluvoxamine and thus, are not to be expected to occur when roflumilast is co-administered with more selective CYP1A2 inhibitors.
Distinction of CYP1A1 and CYP1A2 activity by selective inhibition using fluvoxamine and isosafrole.. A Pastrakuljic; B K Tang; E A Roberts; W Kalow (1997) Biochemical pharmacology display abstract
Ethoxyresorufin O-deethylation (EROD) has been used as a specific probe for CYP1A1 and CYP1A2. Selective inhibition of one of these cytochromes P450 may differentiate their activity in human liver. Four inhibitors were chosen to examine the selective inhibition of EROD activity, using cDNA of CYP1A1 and CYP1A2. The two flavones, alpha-naphthoflavone and apigenin, while differing in potency, inhibited expressed human CYP1A1, CYP1A2, and human liver microsomes to a similar extent. Isosafrole and fluvoxamine were found to inhibit CYP1A2 selectively, with Ki values of 14 and 800 times, respectively, lower than those for CY1A1. A set of equations was developed to estimate both CYP1A1 and CYP1A2 activity. Levels of CYP1A2 in four human liver specimens ranged from 44.4 to 76.7 pmol/mg protein, which significantly correlated with phenacetin O-deethylase activity (r = 0.99; P < 0.001). Low levels of CYP1A1 activity were present in all four investigated livers, ranging from 0.4 to 2.7 pmol/mg protein.
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.
Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping.. A D Kashuba; A N Nafziger; G L Kearns; J S Leeder; R Gotschall; M L RocciJr; R W Kulawy; D J Beck; J S BertinoJr (1998) Clinical pharmacology and therapeutics display abstract
OBJECTIVE: To determine the effect of 150 mg/day fluvoxamine on the activities of CYP1A2, CYP2D6, CYP3A, N-acetyltransferase-2 (NAT2), and xanthine oxidase (XO) by phenotyping with caffeine, dextromethorphan, and midazolam. METHODS: Oral caffeine (2 mg/kg), oral dextromethorphan (30 mg), and intravenous midazolam (0.025 mg/kg) were administered to 10 white male volunteers every 14 days for 4 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 4 complete cycles (8 total phenotyping measures). The first 6 phenotyping measures were used to establish baseline activity. Subjects were given 150 mg/day fluvoxamine for the fourth month or cycle of the study. Enzyme activity for CYP1A2, CYP2D6, NAT2, and XO was expressed as urinary metabolite ratios. Midazolam plasma clearance was used to express CYP3A activity. RESULTS: No difference between baseline and weeks 2 and 4 of fluvoxamine therapy was observed for NAT2 or XO metabolite ratios. For CYP1A2, CYP2D6, and CYP3A phenotypes, significant differences existed between baseline and fluvoxamine therapy. For CYP1A2, the mean urinary metabolite ratio (+/-SD) was 7.53 +/- 7.44 at baseline and 4.30 +/- 2.82 with fluvoxamine ( P = .012). Mean CYP2D6 molar urinary dextromethorphan ratios before and after fluvoxamine therapy were 0.00780 +/- 0.00694 and 0.0153 +/- 0.0127, respectively (P = .011). Midazolam clearance decreased from 0.0081 +/ 0.0024 L/min/kg at baseline to 0.0054 +/- 0.0021 L/min/kg with therapy (P = .0091). For CYP1A2, CYP2D6, and CYP3A, fluvoxamine therapy changed the phenotyping measures by a median of -44.4%, 123.5%, and -34.4%, respectively. CONCLUSIONS: We concluded that fluvoxamine may cause significant inhibition of CYP1A2, CYP2D6, and CYP3A activity. This metabolic inhibition may have serious implications for a variety medications.