It was found that paroxetine, an inhibitor of CYP2D6, increased the bioavailability of galantamine by 40%. The CYP3A4 inhibitors ketoconazole and erythromycin increased the bioavailability of galantamine by 30% and 12%, respectively. Synthesis
Galantamine is produced from natural resources, but also has many industrial syntheses. Companies such as Janssen, Ortho-McNeil Pharmaceutical, Sanochemia Pharmazeutika, Shire, and Takeda Pharmaceutical Company have industrial processes for synthesizing Galantamine. Research
Organophosphate poisoning
The toxicity of organophosphates results primarily from their action as irreversible inhibitors of acetylcholinesterase. Inhibiting acetylcholinesterase causes an increase in acetylcholine, as the enzyme is no longer available to catalyze its breakdown. In the peripheral nervous system, acetylcholine accumulation can cause an overstimulation of muscarinic receptors followed by a desensitization of nicotinic receptors. This leads to severe skeletal muscle fasciculations (involuntary contractions). The effects on the central nervous system include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma. As a reversible acetylcholinesterase inhibitor, galantamine has the potential to serve as an effective organophosphate poisoning treatment by preventing irreversible acetylcholinesterase inhibition. Additionally, galantamine has anticonvulsant properties which may make it even more desirable as an antidote.Research supported in part by the US Army has led to a US patent application for the use of galantamine and/or its derivatives for treatment of organophosphate poisoning. The indications for use of galantamine in the patent application include poisoning by nerve agents "including but not limited to soman, sarin, and VX, tabun, and Novichok agents".
The coadministration of food delays the rate of galantamine absorption, but does not affect the extent of absorption.Plasma protein binding of galantamine is about 18%, which is relatively low. Metabolism
Approximately 75% of a dose of galantamine is metabolised in the liver. In vitro studies have shown that hepatic CYP2D6 and CYP3A4 are involved in galantamine metabolism. Within 24 hours of intravenous or oral administration approximately 20% of a dose of galantamine will be excreted unreacted in the urine.In humans, several metabolic pathways for galantamine exist. These pathways lead to the formation of a number of different metabolites. One of the metabolites that may result can be formed through the glucuronidation of galantamine. Additionally, galantamine may undergo oxidation or demethylation at its nitrogen atom, forming two other possible metabolites. Galantamine can undergo demethylation at its oxygen atom, forming an intermediate which can then undergo glucuronidation or sulfate conjugation. Lastly, galantamine may be oxidized and then reduced before finally undergoing demethylation or oxidation at its nitrogen atom, or demethylation and subsequent glucuronidation at its oxygen atom. For Razadyne ER, the once-a-day formulation, CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers. About 7% of the population has this genetic mutation; however, because the drug is individually titrated to tolerability, no specific dosage adjustment is necessary for this population. Drug interactions
Since galantamine is metabolized by CYP2D6 and CYP3A4, inhibiting either of these isoenzymes will increase the cholinergic effects of galantamine. Inhibiting these enzymes may lead to adverse effects.