Chemical Properties
White Solid
Usage
Anthelmintic, effective against flatworms.
Usage
anthelmintic; EMBAY-8440
Description
Praziquantel (PZQ) is an isoquinoline derivative with most of the biological activity found in the
levo enantiomer. The compound has no activity against nematodes, but it is highly effective
against cestodes and trematodes.
Originator
Cesol ,Merck ,W. Germany ,1980
Definition
ChEBI: 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one is a member of isoquinolines.
Manufacturing Process
15 g of a nickel-aluminum alloy (1:1) is introduced in incremental portions and under agitation into 200 ml of 20% sodium hydroxide solution within 5 minutes; the mixture is maintained at 80°C for 45 minutes, then allowed to settle, decanted off, washed with water, and 1,000 ml of 1% (-)-tartaric acid solution is added thereto, adjusted to pH 5 with 1 N sodium hydroxide solution. The mixture is heated under agitation for 90 minutes to 80°C, decanted, and washed with water and methanol. The thus-obtained (-)tartaric acid-Raney nickel catalyst is added to a solution of 2cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline. The reaction mixture is hydrogenated under normal pressure and at room temperature. After the catalyst has been filtered off and the solvent evaporated, 2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4Hpyrazino[2,1-a]isoquinoline, melting point 136°C to 138°C, is produced.
Brand name
Biltricide (Bayer).
Therapeutic Function
Anthelmintic
Acquired resistance
There is evidence that resistance to praziquantel is emerging
in schistosomes, although there is debate as to whether treatment
failures are due to resistance or innate tolerance.
Pharmaceutical Applications
A synthetic pyrazinoquinoline formulated for oral administration.
It is stable in the dry state, but hygroscopic.
Mechanism of action
Praziquantel is readily absorbed (80% in 24 hours)
after oral administration, with serum concentrations being
maximal in 1 to 3 hours; the drug has a half-life of
0.8 to 1.5 hours. Its bioavailability is reduced by phenytoin
or carbamazepine and increased by cimetidine.
Dexamethasone decreases plasma praziquantel levels
by 50%. Praziquantel is excreted by the kidneys.
Pharmacokinetics
Oral absorption: >80%
Cmax 50 mg/kg oral: 1 mg/L after 1–2 h
Plasma half-life: parent drug: 1–1.5 h
metabolites: 4–6h
Plasma protein binding: 80%
Praziquantel is rapidly absorbed when given orally, but it
undergoes extensive first-pass biotransformation and the concentration
of unchanged drug in plasma is low. The major
metabolite, a 4-hydroxy derivative, retains little to no antiparasitic
activity. About 80% of the oral dose, as parent drug
and its metabolites, is excreted in the urine by the fourth day
post-treatment, 90% of this in 24 h. A higher peak plasma
concentration is achieved in infected people, but other pharmacokinetic
values are unchanged.
Clinical Use
2-(Cyclohexylcarbonyl)-1,2,3,6,7, 11b-hexahydro-4Hpyrazino[2,1-a]isoquinolin-4-one (Biltricide) is a broadspectrumagent that is effective against various trematodes (flukes). It has become the agent of choice for the treatmentof infections caused by schistosomes (blood flukes).
The drug also provides effective treatment for fasciolopsiasis(intestinal fluke), clonorchiasis (Chinese liver fluke),fascioliasis (sheep liver fluke), opisthorchosis (liver fluke),and paragonimiasis (lung fluke). Praziquantel increases cellmembrane permeability of susceptible worms, resulting inthe loss of extracellular calcium. Massive contractions andultimate paralysis of the fluke musculature occurs, followedby phagocytosis of the parasite.
Following oral administration, about 80% of the doseis absorbed. Maximal plasma concentrations are achievedin 1 to 3 hours. The drug is rapidly metabolized in theliver in the first-pass. It is likely that some of the metabolitesare also active. Praziquantel occurs as a white crystallinesolid that is insoluble in water. It is available as600-mg film-coated tablets. The drug is generally welltolerated.
Clinical Use
Praziquantel is an extremely active broad-spectrum
anthelmintic that is well tolerated. It is the most effective
of the drugs used in the treatment of schistosomiasis,
possessing activity against male and female adults
and immature stages. Unlike other agents, it is active
against all three major species (S. haematobium, S. mansoni,
and S. japonicum). In addition, it has activity
against other flukes, such as C. sinensis, Paragonimus
westermani, O. viverrini, and the tapeworms (D. latum,
H. nana, T. saginata, and T. solium). It is not as effective
against F. hepatica. It is used effectively in the treatment
of clonorchiasis and paragonimiasis and is an effective
alternative agent to niclosamide in the treatment of
tapeworm infestations.
Clinical Use
Schistosomiasis
Other trematode infections (except F. hepatica)
Tapeworm infection, including cerebral cysticercosis
Treatment may need to be prolonged in cerebral cysticercosis.
Safety Profile
Poison by intraperitoneal route.Moderately toxic by ingestion and other routes. Humanmutation data reported. When heated to decomposition itemits toxic fumes of NOx.
Synthesis
Praziquantel, 2-(cyclcohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1a]isoquinolin-4-one (38.1.15), is a derivative of pyrazinoquinoline that is made in two ways. According to one of them, 1-aminomethyl-1,2,3,4-tetrahydroisoquinoline is alkylated with chloroacetic acid, and then the resulting amine is acylated with cyclohexanecarbonyl chloride to make 1-(N-carboxymethyl-N-cyclohexylcarbonylaminomethyl)-1,2,3,4-tetra-hydroisoquinoline (38.1.14), which is heated at 150°C to give the desired praziquantel.
Another way of synthesizing this drug begins with isoquinoline, which is reacted with a mixture of cyclohexanecarbonyl chloride / potassium cyanide to make a dihydro derivative of isoquinoline (38.1.16). This is reduced by hydrogen over Raney nickel to give the reduction–reamidation product—the amide 1-(N-cyclohexylcarbonylaminomethyl)- 1,2,3,4-tetrahydroisoquinoline (38.1.17). Acylating this with chloracetic acid chloride gives a chlroacetyl derivative (38.1.18), which when heated in the presence of diethylamine results in an intramolecular alkylation, giving the desired product—prazi quantel.
Veterinary Drugs and Treatments
Praziquantel is indicated for (approved labeling) for the treatment
of Dipylidium caninum, Taenia pisiformis, and Echinococcus granulosis
in dogs, and Dipylidium caninum and Taenia taeniaeformis in
cats. Fasting is not required nor recommended before dosing. A
single dose is usually effective, but measures should be taken to prevent
reinfection, particularly against D. caninum. Praziquantel can
also be used for treating Alaria spp. in dogs and cats and Spirometra
mansonoides infections in cats.
Praziquantel has been used in birds and other animals, but it
is usually not economically feasible to use in large animals. In humans,
praziquantel is used for schistosomiasis, other trematodes
(lung, liver, intestinal flukes) and tapeworms. It is not routinely effective
in treating F. hepatica infections in humans.
Combination products can give a wide spectrum of internal
parasite control in a variety of species.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Antiepileptics: concentration reduced by
carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone.
Antimalarials: concentration reduced by chloroquine.
Ulcer-healing drugs: concentration reduced by
cimetidine.
Metabolism
Praziquantel is rapidly absorbed and undergoes hepatic first-pass metabolism. The metabolites are
either less active or inactive and consist of hydroxylated compounds. In the serum, the major
metabolite appears to be the monohydroxylated 4-hydroxycyclohexylcarboxylate, whereas in the
urine, 50 to 60% of the initial PZQ exists as dihydroxylated products.These
hydroxylation reactions are catalyzed by CYP2B6 and CYP3A4. The metabolites would be
expected to exist in the conjugated form in the urine.
