Chemical Properties
Off White to Light Orange Coloured Solid
Originator
Johnson & Johnson (US)
Definition
ChEBI: 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one is a member of the class of pyridopyrimidines that is 9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one carrying an additional 2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl group at position 2. It is a member of 1,2-benzoxazoles, a heteroarylpiperidine, an organofluorine compound, a pyridopyrimidine and a secondary alcohol.
General Description
Paliperidone, (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(Invega), is essentially insoluble in water and is available asextended-release tablets. Paliperidone is delivered at a constantrate using an osmotic drug release device (OsmoticRelease Oral Systems [OROS]). The absolute bioavailabilityof paliperidone is 28%, and studies in healthy subjects on ahigh-fat, high-calorie meal showed an increase in AUC.Paliperidone is 74% bound to plasma proteins. After a single,1-mg dose of C-paliperidone, 59% of the dose was excretedin the urine as unchanged drug, and 32% of the dose was recoveredas metabolites. Most of the drug (80%) is excreted bythe kidneys. Paliperidone is metabolized by dealkylation, hydroxylation,dehydrogenation, and scission of the benzoxazolering. None of these metabolic pathways account for morethan 10% of the dose. The terminal elimination half-life ofpaliperidone is 23 hours.
Biochem/physiol Actions
Paliperidone is an atypical antipsychotic; active metabolite of risperidone.
Clinical Use
Atypical antipsychotic for schizophrenia
Side effects
The most common adverse events
included tachycardia, QTc prolongation, headache, anxiety, dizziness, tremors,
and insomnia along with the dose-related events of somnolence, orthostatic
hypotension, salivary hypersecretion, and extrapyrimidal disorder. Weight gain
was also observed in 6–9% of patients which may be attributable to paliperidone’s
lower affinity for H1-histaminergic and a1- and a2-adrenergic receptors. Patients
with renal impairment require dose adjustments since elimination of paliperidone
is altered. Paliperidone is contraindicated in patients with a hypersensitivity to
risperidone. Concomitant use of class III antiarrhythmic agents should be avoided
since this may result in additive QT interval prolongation. Also, loss of levodopa
efficacy is expected with this D2 antagonist.
Synthesis
The synthesis of paliperidone involves the reaction of
2-acetyl-g-butyrolactone with 2-amino-3-benzyloxypyridine in the presence of
phosphoryl chloride. The benzyl protecting group of the intermediate 9-benzyloxy-
3-(2-chloroethyl)-2-methylpyrido[1,2-a]pyrimidin-4-one is then removed by
hydrogenolysis over Pd/C followed by the nucleophilic displacement of the
chlorine with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole to provide racemic
paliperidone. While paliperidone can be resolved, both enantiomers are
equipotent and interconvert in vivo obviating the need for separation.
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: increased risk of convulsions with
tramadol; enhanced hypotensive and sedative
effects with opioids; increased risk of ventricular
arrhythmias with methadone.
Anti-arrhythmics: increased risk of ventricular
arrhythmias when given with anti-arrhythmics that
prolong the QT interval.
Antidepressants: increases concentration of tricyclics
(possibly increased risk of ventricular arrhythmias).
Antiepileptics: antagonise anticonvulsant effect
(convulsive threshold lowered); concentration
reduced by carbamazepine.
Antimalarials: avoidance of antipsychotics advised by
manufacturer of artemether/lumefantrine.
Antipsychotics: possible increased risk of ventricular
arrhythmias with risperidone.
Antivirals: concentration possibly increased by ritonavir.
Atomoxetine: increased risk of ventricular
arrhythmias with atomoxetine.
Cytotoxics: increased risk of ventricular arrhythmias
with arsenic trioxide.
References
1) Beijsterveldt?et al.?(1994),?Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat; Psychopharmacology,?114?53 DOI:
10.1007/BF022454442) Leysen?et al. (1994),?Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity; J. Clin. Psychiatry,?55?suppl: 5 PMID:
75209083) Schotte?et al.?(1996),?Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding; Psychopharmacology (Berl.),?124?57 DOI:
10.1007/BF02245606
