フルオキセチン 化学特性,用途語,生産方法
用途
フルオキセチン (英: Fluoxetine) は、選択的セロトニン再取り込み阻害薬（SSRI）に分類される抗うつ薬の1つである。
効能
抗うつ薬, 選択的セロトニン再取り込み阻害薬
使用
antibacterial
生物学の機能
Fluoxetine (Prozac) is given in the morning because of
its potential for being activating and causing insomnia.
Food does not affect its systemic bioavailability and
may actually lessen the nausea reported by some patients.
Fluoxetine is highly bound to serum proteins and
may interact with other highly protein bound drugs. It is
demethylated in the liver to form an active metabolite,
norfluoxetine. Inactive metabolites are excreted by the
kidney.Doses must be reduced in patients with liver disease.
The slow elimination of fluoxetine and norfluoxetine
lead to special clinical concerns when adjusting
doses and discontinuing this medication. Steady state is
not reached until 4 to 6 weeks, and similarly, complete
elimination takes 4 to 6 weeks after discontinuation of
the medication. A 4- to 6-week waiting period should be
permitted before starting a medication with potential
for an interaction with fluoxetine, such as a monoamine
oxidase inhibitor (MAOI). Additionally, fluoxetine is a
potent inhibitor of cytochrome P450 2D6 and can significantly
elevate levels of drugs metabolized by this
route. Thus, coadministration of drugs with a narrow
therapeutic index, such as TCAs and type 1C antiarrhythmics,
including flecainide and propafenone, are a
particular concern.
一般的な説明
In fluoxetine (Prozac), protonated in vivo, the protonatedamino group can H-bond to the ether oxygen electrons, whichcan generate the β-arylamino–like group, with the other arylserving as the characteristic “extra” aryl. The S-isomer ismuch more selective for SERT than for NET. The majormetabolite is the N-demethyl compound, which is as potent asthe parent and more selective (SERT versus NET).
Therapy for 2 or more weeks is required for the antidepressanteffect. Somatodendritic 5-HT
1A autoreceptor desensitizationwith chronic exposure to high levels of 5-HT isthe accepted explanation for the delayed effect for this andother serotonin reuptake inhibitors.
作用機序
Fluoxetine is a potent and selective inhibitor of 5-HT reuptake, but not of NE or dopamine uptake in the CNS.
Its mechanism of action is common to the SSRIs. Fluoxetine does not interact directly with postsynaptic 5-HT
receptors and has weak affinity for the other neuroreceptors. Both enantiomers of fluoxetine display similar
affinities for human SERT. The NE:5-HT selectivity ratio, however, indicates that the S-enantiomer is
approximately 100 times more selective for SERT inhibition than the R-enantiomer. The R-(+)-stereoisomer is
approximately eight times more potent an inhibitor of SERT together with a longer duration of action than the
S-(–)-isomer. However, the S-(–)-norfluoxetine metabolite is seven times more potent as an inhibitor of the
5-HT transporter than the R-(+)-metabolite, with a selectivity ratio approximately equivalent to that of
S-fluoxetine.
薬物動態学
The pharmacokinetics of fluoxetine fit the general characteristics of the SSRIs. Of particular
importance is its long half-life contributing to its nonlinear pharmacokinetics. In vitro studies show that
fluoxetine and norfluoxetine are potent inhibitors of CYP2D6 and CYP3A4 and less potent inhibitors of
CYP2C9, CYP2C19 and CYP1A2. Fluoxetine is metabolized primarily by CYP2D6 N-demethylation to its active
metabolite norfluoxetine and, to a lesser extent, O-dealkylation to form the inactive metabolite
p-trifluoromethylphenol. Following oral administration, fluoxetine and its metabolites are excreted principally
in urine, with approximately 73% as unidentified metabolites, 10% as norfluoxetine, 10% as norfluoxetine
glucuronide, 5% as fluoxetine N-glucuronide, and 2% as unmetabolized drug.
Both R- and S-Norfluoxetine were less potent than the corresponding enantiomers of fluoxetine as inhibitors
of NE uptake. Inhibition of 5-HT uptake in cerebral cortex persisted for more than 24 hours after
administration of S-norfluoxetine similarly to fluoxetine. Thus, S-norfluoxetine is the active N-demethylated
metabolite responsible for the persistently potent and selective inhibition of 5-HT uptake in vivo.
The pharmacokinetics of fluoxetine in healthy geriatric individuals do not differ substantially from those in
younger adults. Because of its relatively long half-life and nonlinear pharmacokinetics, the possibility of
altered pharmacokinetics in geriatric individuals could exist, particularly those with systemic disease and/or in
those receiving multiple medications concurrently. The elimination half-lives of fluoxetine and norfluoxetine do
not appear to be altered substantially in patients with renal or hepatic impairment.
薬理学
Fluoxetine is a phenylpropylamine that inhibits the neuronal reuptake of serotonin, which
presumably has a direct relationship on antidepressant activity. This compound has either no effect or a small effect on the neuronal reuptake of norepinephrine and dopamine. In
addition, it does not bind to cholinergic, histaminergic, or α-adrenergic receptors, which is
believed to be the cause of tricyclic antidepressant side effects.
臨床応用
Fluoxetine is a 3-phenoxy-3-phenylpropylamine that exhibits selectivity and high affinity for human SERT and
low affinity for NET. It is marketed as a racemic mixture of R- and S-fluoxetine. Its selectivity for
SERT inhibition depends on the position of the substituent in the phenoxy ring.
薬物相互作用
Fluoxetine and its norfluoxetine metabolite, like many other drugs metabolized by CYP2D6, inhibit the activity
of CYP2D6 and, potentially, may increase plasma concentrations of concurrently administered drugs that also
are metabolized by this enzyme. Fluoxetine may make normal CYP2D6 metabolizers resemble poor
metabolizers. Fluoxetine can inhibit its own CYP2D6 metabolism, resulting in higher-than-expected plasma
concentrations during upward dose adjustments. Therefore, switching from fluoxetine to another SSRI or
other serotonergic antidepressant requires a washout period of at least 5 weeks or a lowerthan-recommended initial dose with monitoring for adverse events.
Fluoxetine is highly protein bound and may affect the free plasma concentration and, thus, the
pharmacological effect of other highly protein-bound drugs (e.g., warfarin sodium).
フルオキセチン 上流と下流の製品情報
原材料
準備製品