Modafinil
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🧬 Receptor activity
Mechanism of action
The exact mechanism of action is unclear, although <i>in vitro</i> studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by directly stimulating the receptors.
The precise mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil has wake-promoting actions similar to sympathomimetic agents like amphetamine and methylphenidate, although the pharmacologic profile is not identical to that of sympathomimetic amines. Modafinil has weak to negligible interactions with receptors for norepinephrine, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, and benzodiazepines. Modafinil also does not inhibit the activities of MAO-B or phosphodiesterases II-V. Modafinil-induced wakefulness can be attenuated by the á1-adrenergic receptor antagonist prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to á-adrenergic agonists, such as the rat vas deferens preparation. Modafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil.
Modafinil is a well-tolerated medication for excessive sleepiness, attention-deficit disorder, cocaine dependence and as an adjunct to antidepressants with low propensity for abuse. ... The modafinil action on identified dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra (SN) of rat brain slices /was examined/. Modafinil (20 microM) inhibited the firing of dopaminergic, but not GABAergic neurons. This inhibition was maintained in the presence of tetrodotoxin and was accompanied by hyperpolarization. Sulpiride (10 microM), a D2-receptor antagonist, but not prazosine (20 microM, an alpha1-adrenoreceptor blocker) abolished the modafinil action. Inhibition of dopamine reuptake with a low dose of nomifensine (1 microM) reduced the firing of DA neurons in a sulpiride-dependent manner and blunted the effect of modafinil. On acutely isolated neurons, modafinil evoked D2-receptor-mediated outward currents in tyrosine-hydroxylase positive cells, identified by single-cell RT-PCR, which reversed polarity near the K(+) equilibrium potential and were unchanged in the presence of nomifensine. Thus modafinil directly inhibits DA neurons through D2 receptors.
Modafinil is a wakefulness-promoting drug that improves the alertness levels in narcolepsy; however, the molecular mechanism of action remains to be elucidated. We found that after a single icv injection of modafinil (10 ug/5 uL) the extracellular levels of dopamine (DA) and l-DOPA collected from the nucleus accumbens were increased and decreased, respectively. Separately, the icv administration of modafinil (10 microg/5 uL) to rats enhanced wakefulness (W) whereas diminished sleep during 4hr. Lastly, the alertness induced by modafinil was partially antagonized by the sleep-inducing endocannabinoid anandamide (ANA). We conclude that modafinil enhances the extracellular levels of DA, promotes W and its effects on sleep are partially blocked by ANA.
Modafinil is an increasingly popular wake-promoting drug used for the treatment of narcolepsy, but its precise mechanism of action is unknown. To determine potential pathways via which modafinil acts, we administered a range of doses of modafinil to rats, recorded sleep/wake activity, and studied the pattern of neuronal activation using Fos immunohistochemistry. To contrast modafinil-induced wakefulness with spontaneous wakefulness, we administered modafinil at midnight, during the normal waking period of rats. To determine the influence of circadian phase or ambient light, we also injected modafinil at noon on a normal light/dark cycle or in constant darkness. We found that 75 mg/kg modafinil increased Fos immunoreactivity in the tuberomammillary nucleus (TMN) and in orexin (hypocretin) neurons of the perifornical area, two cell groups implicated in the regulation of wakefulness. This low dose of modafinil also increased the number of Fos-immunoreactive (Fos-IR) neurons in the lateral subdivision of the central nucleus of the amygdala. Higher doses increased the number of Fos-IR neurons in the striatum and cingulate cortex. In contrast to previous studies, modafinil did not produce statistically significant increases in Fos expression in either the suprachiasmatic nucleus or the anterior hypothalamic area. These observations suggest that modafinil may promote waking via activation of TMN and orexin neurons, two regions implicated in the promotion of normal wakefulness. Selective pharmacological activation of these hypothalamic regions may represent a novel approach to inducing wakefulness.
For more Mechanism of Action (Complete) data for MODAFINIL (6 total), please visit the HSDB record page.
Pharmacodynamics
Modafinil is a stimulant drug marketed as a 'wakefulness promoting agent' and is one of the stimulants used in the treatment of narcolepsy. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins, whose neurons are activated by modafinil. The prexin neuron activation is associated with psychoactivation and euphoria. Modafinil is not indicated for complaints of lack of energy or fatigue; but it appears to be very helpful for some patients. Also, it has been used in the treatment of hypersomnia, a disorder in which patients lack the capacity for meaningful sleep and may require ten or more hours per day. Recent studies have have found that modafinil may help recovering cocaine addicts fight their addiction.
Pharmacokinetics
Half-life
23-215 hours
Elimination: Effectively, about 15 hours after multiple dosing; the elimination half life of the levo-isomer is about three times that of the dextro-isomer.
... Modafinil was rapidly absorbed after oral dosing and slowly cleared (half life approximately 11-14 hr) from the body.
Absorption
Rapid following oral administration.
The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites.
0.9 L/kg
An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. ... Modafinil was rapidly absorbed after oral dosing and slowly cleared (half life approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.
It is not known whether modafinil or its metabolites are distributed into milk.
Modafinil is well distributed in body tissue with an apparent volume of distribution (approximately 0.9 L/kg) larger than the volume of total body water (0.6 L/kg). In human plasma, in vitro, modafinil is moderately bound to plasma protein (approximately 60%, mainly to albumin). At serum concentrations obtained at steady state after doses of 200 mg/day, modafinil exhibits no displacement of protein binding of warfarin, diazepam or propranolol. Even at much larger concentrations (1000uM; > 25 times the Cmax of 40uM at steady state at 400 mg/day), modafinil has no effect on warfarin binding. Modafinil acid at concentrations >500 uM decreases the extent of warfarin binding, but these concentrations are >35 times those achieved therapeutically.
Metabolism
Hepatic
The major route of elimination is metabolism (approximately 90%), primarily by the liver, with subsequent renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of modafinil. Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound. In a clinical study using radiolabeled modafinil, a total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in the feces). The largest fraction of the drug in urine was modafinil acid but at least six other metabolites were present in lower concentrations. Only two metabolites reach appreciable concentrations in plasma, i.e., modafinil acid and modafinil sulfone. In preclinical models, modafinil acid, modafinil sulfone, 2-((diphenylmethyl)sulfonyl)acetic acid and 4-hydroxy modafinil, were inactive or did not appear to mediate the arousal effects of modafinil.
Based on in vitro data, modafinil is metabolized partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4).
Hepatic
Route of Elimination: The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites.
Half Life: 23-215 hours
Protein binding
60%
External links
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