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Drug-Target Interaction

Drug

show drug details
PubChem ID:5361192
Structure:
Synonyms:
2-[(Z)-[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethana
5-Methoxy-4'-(trifluoromethyl)valerophenone (E)-O-(2-aminoethyl)oxime
AC1NSF25
BRD-K72676686-103-01-8
CAS-61718-82-9
Fluvoxamine
Lopac-F-2802
NCGC00015431-01
NCGC00015431-02
NCGC00018193-01
NCGC00018193-02
NCGC00018193-03
NCGC00021870-02
Tocris-1033
ATC-Codes:
Side-Effects:
Side-EffectFrequency
sweating increased1.0
malaise1.0
weight gain1.0
vertigo0.85857147
palpitations0.6426315
constipation0.63500005
tremor0.5928572
abdominal pain0.5273913
nausea0.51354843
agitation0.4896001
insomnia0.47599998
headache0.475
somnolence0.4593549
dry mouth0.45310357
nervousness0.44827592
vomiting0.447143
asthenia0.4374195
dyspepsia0.42966685
anorexia0.42466673
dizziness0.42451614
diarrhea0.42322582
anxiety0.40612903
weight loss0.13499999
upper respiratory infection0.09
tachycardia0.08615385
syncope0.086153835
amnesia0.086153835
hypotension0.086153835
hypertension0.081428565
sinusitis0.07923079
cough0.07923078
edema0.07784618
sweating0.062222224
abscess0.03
toothache0.03
blurred vision0.03
urinary frequency0.020000001
amblyopia0.02
viral infection0.02
flatulence0.019999998
flu syndrome0.016666668
myalgia0.015714284
libido decreased0.015652176
impotence0.014999999
pharyngitis0.013846155
dysphagia0.013333333
dyspnea0.013333332
chest pain0.01153846
paresthesia0.01142857
tooth disorder0.011157895
neurosis0.010769229
hemorrhoids0.01
hypothyroidism0.01
heart failure0.01
tenosynovitis0.01
muscle spasm0.01
hypochondriasis0.01
seborrhea0.01
leukocytosis0.01
visual field defect0.01
hypercholesterolemia0.01
otitis media0.01
hypersomnia0.01
sleep disorder0.01
agoraphobia0.01
phobia0.01
cold extremities0.01
gait unsteady0.01
bursitis0.01
photosensitivity0.01
contracture0.01
hoarseness0.01
cardiomyopathy0.01
ulcer0.01
exfoliative dermatitis0.01
allergic reaction0.009999999
drug dependence0.009999999
abnormal gait0.009999999
arthralgia0.009999999
metrorrhagia0.009999999
rhinitis0.009999999
eructation0.009999999
urinary incontinence0.009999999
infection0.009999999
angina pectoris0.009999999
hypersensitivity0.009999999
dysuria0.009999999
ataxia0.009999999
back pain0.009999999
confusion0.009999999
suicide attempt0.009999999
peripheral edema0.009999999
postural hypotension0.009999999
migraine0.009999999
gastritis0.009999999
gastroenteritis0.009999999
increased salivation0.009999999
colitis0.009999999
hyperacusis0.009999999
pruritis0.009999999
hallucinations0.009999999
neck pain0.009999999
abnormal vision0.009999999
tetany0.009999999
pain0.009071431
chills0.0084
arthrosis0.0077499994
ecchymosis0.0070
angioedema0.0060
urinary retention0.0054999986
menorrhagia0.0051428564
bronchitis0.004666667
laryngitis0.004615383
fever0.0044838707
eruption0.0043750005
epistaxis0.0042857137
urinary tract infection0.0037142858
polyuria0.0037142858
asthma0.0035714284
dehydration0.00325
gingivitis0.002999999
acne0.002999999
voice alteration0.0025000002
myocardial infarct0.0025000002
bradycardia0.0025
liver function test abnormal0.0024615387
diplopia0.0022857145
hemiplegia0.0022857145
dyskinesia0.0022857145
ear pain0.0022857145
thrombocytopenia0.0022857145
hiccups0.0022857145
gastrointestinal haemorrhage0.0022857145
psychosis0.0022857145
esophagitis0.0022857145
glossitis0.0022857145
stomatitis0.0022857145
delirium0.0022857145
eye pain0.0022857145
rectal haemorrhage0.0022857145
dry eyes0.0022857145
pneumonia0.0022857145
lymphadenopathy0.0022857145
paralysis0.0022857145
arthritis0.0022857145
anemia0.0022857145
breast pain0.0022857145
melena0.0022857145
neck rigidity0.0022857145
conjunctivitis0.0022857145
photophobia0.0022857145
cystitis0.0022857145
deafness0.0022857145
neuralgia0.0022857145
convulsion0.002285714
furunculosis0.0016923079
eczema0.0016923079
urticaria0.0016923076
dry skin0.0016923076
alopecia0.0016923076
agranulocytosis0.0010
hyperglycemia0.0010
tenesmus0.0010
leukopenia0.0010
carcinoma0.0010
cholelithiasis0.0010
pulmonary disease0.0010
serotonin syndrome0.0010
bone pain0.0010
hyperesthesia0.0010
lactate dehydrogenase increased0.0010
herpes zoster0.0010
coma0.0010
mouth ulceration0.0010
hematospermia0.0010
herpes simplex0.0010
pathological fracture0.0010
corneal ulcer0.0010
blepharitis0.0010
leg cramps0.0010
av block0.0010
myopathy0.0010
amenorrhea0.0010
anaphylactic reaction0.0010
hypokalemia0.0010
aplastic anemia0.0010
hypoglycemia0.0010
apnea0.0010
tardive dyskinesia0.0010
arrhythmia0.0010
jaundice0.0010
kidney pain0.0010
hyperlipidemia0.0010
kidney calculus0.0010
neuropathy0.0010
acute renal failure0.0010
rheumatoid arthritis0.0010
lacrimation disorder0.0010
urinary urgency0.0010
retinal detachment0.0010
pericarditis0.0010
embolus0.0010
hematemesis0.0010
toxic epidermal necrolysis0.0010
phlebitis0.0010
hyponatremia0.0010
porphyria0.0010
fecal incontinence0.0010
supraventricular extrasystoles0.0010
cerebrovascular accident0.0010
priapism0.0010
stevens - johnson syndrome0.0010
halitosis0.0010
psoriasis0.0010
purpura0.0010
shock0.0010
goiter0.0010
torticollis0.0010
cholecystitis0.0010
pelvic pain0.0010
obesity0.0010
nocturia0.0010
hepatitis0.0010
hernia0.0010
cyst0.0010
neoplasia0.0010
peripheral vascular disorder0.0010
coronary artery disease0.0010
diabetes mellitus0.0010
haemorrhage0.0010
dysmenorrhea0.0010
hematuria0.0010
pancreatitis0.0010
hemoptysis0.0010
vaginitis0.0010
vasculitis0.0010
ventricular tachycardia0.0010
dysarthria0.0010
stupor0
thinking abnormal0
depersonalization0
emotional lability0
apathy0
delusions0
euphoria0
siadh0
pms0
galactorrhea0
herpes0
major depressive disorder0
tinnitus0
fatigue0
vaginal hemorrhage0
sexual dysfunction0
manic0

Target

show target details
Uniprot ID:CP1A2_HUMAN
Synonyms:
CYPIA2
Cytochrome P450 1A2
P(3)450
P450 4
P450-P3
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:2HI4
Structure:
2HI4

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----

References:

012828569
015845683
10192756
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.
10492058
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.
11180037
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.
11270913
11791895
12352274
12695344
Comparison of in vitro and in vivo inhibition potencies of fluvoxamine toward CYP2C19.. Caiping Yao; Kent L Kunze; William F Trager; Evan D Kharasch; Renť H Levy (2003) Drug metabolism and disposition: the biological fate of chemicals display abstract
A previous study suggested that fluvoxamine inhibition potency toward CYP1A2 is 10 times greater in vivo than in vitro. The present study was designed to determine whether the same gap exists for CYP2C19, another isozyme inhibited by fluvoxamine. In vitro studies examined the effect of nonspecific binding on the determination of inhibition constant (K(i)) values of fluvoxamine toward CYP2C19 in human liver microsomes and in a cDNA-expressed microsomal (Supersomes) system using (S)-mephenytoin as a CYP2C19 probe. K(i) values based on total added fluvoxamine concentration (K(i,total)) and unbound fluvoxamine concentration (K(i,ub)) were calculated, and interindividual variability in K(i) values was examined in six nonfatty livers. K(i,total) values varied with microsomal protein concentration, whereas the corresponding K(i,ub) values were within a narrow range (70-80 nM). In vivo inhibition constants (K(i)iv) were obtained from a study of the disposition of a single oral dose (100 mg) of the CYP2C19 probe (S)-mephenytoin in 12 healthy volunteers receiving fluvoxamine at 0, 37.5, 62.6, and 87.5 mg/day to steady state. In this population, the ratio of (S)-4-hydroxy-mephenytoin formation clearances (uninhibited/inhibited) was positively correlated with fluvoxamine average steady-state concentration with an intercept of 0.85 (r(2) = 0.88, p < 0.001). The mean (+/-S.D.) values of K(i)iv based on total and unbound plasma concentrations were 13.5 +/- 5.6 and 1.9 +/- 1.1 nM, respectively. Comparison of in vitro and in vivo K(i) values, based on unbound fluvoxamine concentrations, suggests that fluvoxamine inhibition potency is roughly 40 times greater in vivo than in vitro.
14642738
14703714
15199661
15496639
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.
15845683
The effect of erythromycin and fluvoxamine on the pharmacokinetics of intravenous lidocaine.. Klaus T Olkkola; Mika H Isohanni; Katri Hamunen; Pertti J Neuvonen (2005) Anesthesia and analgesia display abstract
Inhibitors of CYP3A4 (cytochrome P450 3A4) have a minor effect on lidocaine pharmacokinetics. We studied the effect of coadministration of the antidepressant fluvoxamine (CYP1A2 inhibitor) and antimicrobial drug erythromycin (CYP3A4 inhibitor) on lidocaine pharmacokinetics in a double-blind, randomized, three-way crossover study. Nine volunteers ingested daily 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos for 5 days. On day 6, 1.5 mg/kg lidocaine was administered IV over 60 min. Concentrations of lidocaine and its major metabolite monoethylglycinexylidide were measured for 10 h. Fluvoxamine alone decreased the clearance of lidocaine by 41% (P < 0.001) and prolonged its elimination half-life from 2.6 to 3.5 h (P < 0.01). During the combination of fluvoxamine and erythromycin, lidocaine clearance was 53% smaller than during placebo (P < 0.001) and 21% smaller than during fluvoxamine alone (P < 0.05). During the combination phase the half-life of lidocaine (4.3 h) was longer than during the placebo (2.6 h; P < 0.001) or fluvoxamine (3.5 h; P < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of lidocaine and may increase the risk of lidocaine toxicity. Concomitant use of both fluvoxamine and a CYP3A4 inhibitor such as erythromycin can further increase plasma lidocaine concentrations by decreasing its clearance.
15905806
Interaction study between enoxacin and fluvoxamine.. Toshiki Kunii; Takashi Fukasawa; Norio Yasui-Furukori; Toshiaki Aoshima; Akihito Suzuki; Tomonori Tateishi; Yoshimasa Inoue; Koichi Otani (2005) Therapeutic drug monitoring display abstract
Authors examined a possible interaction between enoxacin, an inhibitor of cytochrome P4501A2, and fluvoxamine (FLV), a substrate for this enzyme. Ten healthy male volunteers received enoxacin 200 mg/d or placebo for 11 days in a double-blind randomized crossover manner, and on the eighth day they received a single oral 50-mg dose of FLV. Blood samplings and pharmacodynamic evaluation were conducted up to 72 hours after FLV dosing. Plasma concentrations of FLV and its active metabolite fluvoxamino acid (FLA) were measured by high-performance liquid chromatography. Enoxacin significantly increased the plasma concentrations at 2 hours (placebo versus enoxacin, mean+/-SD: 4.4+/-2.4 vs 7.0+/-4.1 ng/mL, P
16893613
Co-administration of ramelton and fluvoxamine to increase levels of interleukin-2.. Richard E Kast; Eric Lewin Altschuler (2006) Medical hypotheses display abstract
Ramelton is a medication recently approved by the FDA for treatment of insomnia. Ramelton is an analogue of melatonin with a higher affinity even than that of the natural ligand. Clinically this potentially strong effect of the ligand is blunted by the fact that upon oral ingestion there is first pass metabolism of greater than 95%. This liver metabolism is mediated by the CYP1A2 enzyme. It turns out that the medication fluvoxamine approved by the FDA for the treatment of obsessive compulsive disorder is a potent inhibitor of the CYP1A2 enzyme, with the effect that co-administration of ramelton and fluvoxamine increases blood levels of ramelton by 100-200 fold. It turns out that lymphocytes bear the melatnonin receptors and stimulation of these receptors on lymphocytes cause the lymphocytes to elaborate the pro-inflammatory cytokine interleukin-2 (Il-2). Thus, here we point out that co-administration of ramelton and modest doses of fluvoxamine may be able to smoothly produce increased levels of Il-2, this may be useful in diseases and conditions such as metastatic cancer and maintenance of suppression of the HIV virus.
17596106
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.
17596106
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.
7974626
Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service.. M Jerling; L LindstrŲm; U Bondesson; L Bertilsson (1994) Therapeutic drug monitoring display abstract
Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups--patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.
8466541
Fluvoxamine is a potent inhibitor of cytochrome P4501A2.. K BrÝsen; E Skjelbo; B B Rasmussen; H E Poulsen; S Loft (1993) Biochemical pharmacology display abstract
Fluvoxamine is a new antidepressant and selectively inhibits serotonin reuptake (SSRI). The present study demonstrates that fluvoxamine is a very potent inhibitor of the high-affinity O-deethylation of phenacetin, which is catalysed by cytochrome P4501A2 (CYP1A2), in microsomes from three human livers. Thus, the apparent inhibitor constant of fluvoxamine, Ki, ranged from 0.12 to 0.24 microM. Seven other SSRIs, citalopram, N-desmethylcitalopram, fluoxetine, norfluoxetine, paroxetine, sertraline and litoxetin either did not inhibit or were weak inhibitors of the O-deethylation of phenacetin. Our findings explain the mechanism of the pharmacokinetic interactions between fluvoxamine and drugs that are metabolized by CYP1A2, e.g. theophylline and imipramine.
8466541
Fluvoxamine is a potent inhibitor of cytochrome P4501A2.. K BrÝsen; E Skjelbo; B B Rasmussen; H E Poulsen; S Loft (1993) Biochemical pharmacology display abstract
Fluvoxamine is a new antidepressant and selectively inhibits serotonin reuptake (SSRI). The present study demonstrates that fluvoxamine is a very potent inhibitor of the high-affinity O-deethylation of phenacetin, which is catalysed by cytochrome P4501A2 (CYP1A2), in microsomes from three human livers. Thus, the apparent inhibitor constant of fluvoxamine, Ki, ranged from 0.12 to 0.24 microM. Seven other SSRIs, citalopram, N-desmethylcitalopram, fluoxetine, norfluoxetine, paroxetine, sertraline and litoxetin either did not inhibit or were weak inhibitors of the O-deethylation of phenacetin. Our findings explain the mechanism of the pharmacokinetic interactions between fluvoxamine and drugs that are metabolized by CYP1A2, e.g. theophylline and imipramine.
9105404
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.
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9205822
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.
9617
9757149
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.