Albendazole

Absorption

Poorly absorbed from the gastrointestinal tract due to its low aqueous solubility. Oral bioavailability appears to be enhanced when coadministered with a fatty meal (estimated fat content 40 g)

Toxicity

Symptoms of overdose include elevated liver enzymes, headaches, hair loss, low levels of white blood cells (neutropenia), fever, and itching.

Chemical properties

Albendazole occurs as a white to faintly yellowish powder. It is practically insoluble in water and alcohol, very slightly soluble in ether and dichloromethane, but freely soluble in anhydrous formic acid.

Originator

Zentel ,SK and F ,France ,1981

The Uses of Albendazole

Albendazole is a derivative of benzimidazole, is a drug with a broad antihelmintic spectrum. It exhibits an antihelmintic effect against sensitive cestodes and nematodes by blocking the process of glucose uptake by the parasites, which is expressed in the depletion of glycogen reserves and subsequent reduction in the level of adenosintriphophate. As a result, the parasite stops moving and dies. It is used upon infection of Acaris lumbricoides, Ancylostoma duodenale, Necator americanus, Enterobius vermicularis, and Trichuris trichiura. Synonyms of this drug are SKF 62979 and others.

Background

Albendazole is a benzimidazole broad-spectrum anthelmintic structurally related to mebendazole that is effective against many diseases.

Indications

For the treatment of parenchymal neurocysticercosis due to active lesions caused by larval forms of the pork tapeworm, Taenia solium and for the treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the larval form of the dog tapeworm, Echinococcus granulosus.

Indications

Albendazole appears to cause cytoplasmic microtubular degeneration, which in turn impairs vital cellular processes and leads to parasite death.There is some evidence that the drug also inhibits helminth-specific ATP generation by fumarate reductase.

Definition

ChEBI: Albendazole is a carbamate ester that is methyl 1H-benzimidazol-2-ylcarbamate substituted by a propylsulfanyl group at position 5. It is commonly used in the treatment of parasitic worm infestations. It has a role as a tubulin modulator, a microtubule-destabilising agent and an anthelminthic drug. It is a carbamate ester, a benzimidazolylcarbamate fungicide, an aryl sulfide and a member of benzimidazoles.

Manufacturing Process

A mixture of 6.65 g of 3-chloro-6-nitroacetanilide, 3.2 ml of propylmercaptan, 5.6 g of 50% sodium hydroxide and 100 ml of water is heated at reflux overnight. The cooled mixture is filtered to give the desired 2-nitro-5- propylthioaniline, MP 69.5-71.5°C after recrystallization from ethanol then hexane-ether. NMR (CDCl3) 40%.
The aniline (2.5 g) is hydrogenated with 1.9 ml of concentrated hydrochloric acid, 100 ml ethanol and 5% palladium-on-charcoal to give 4-propylthio-ophenylene- diamine hydrochloride.
A mixture of 2.5 ml of 50% sodium hydroxide in 5 ml of water is added to a mixture of 1.9 g of cyanamide, 2.2 g of methylchloroformate, 3.5 ml of water and 3 ml of acetone over 45 minutes below 10°C, pH raised to 6.5. A molar equivalent solution of the diamine in 100 ml of ethanol is added. The mixture is heated until the easily volatile solvents are expelled, to about 85°C, then maintained at this temperature with some water added for one-half hour. The product, methyl 5-propylthio-2-benzimidazolecarbamate, is separated, washed to give a colorless crystalline solid, MP 208-210°C.

brand name

Albenza (GlaxoSmithKline).

Therapeutic Function

Anthelmintic

Antimicrobial activity

Albendazole is active against trichostrongyles and exhibits useful activity against tissue-dwelling larvae of Trichinella spiralis, larvae of animal hookworms (causing cutaneous larva migrans) and microfilariae of various filarial species. It also exhibits some activity against cysticercosis and hydatid stages of Echinococcus granulosus and Echinococcus multilocularis. It has been successfully used in infections with the protozoon Giardia lamblia and for microsporidiosis.

General Description

Albendazole occurs as a white crystalline powder that isvirtually insoluble in water. The oral absorption of albendazoleis enhanced by a fatty meal. The drug undergoes rapidand extensive first-pass metabolism to the sulfoxide, whichis the active form in plasma. The elimination half-life ofthe sulfoxide ranges from 10 to 15 hours. Considerable biliaryexcretion and enterohepatic recycling of albendazolesulfoxide occurs. Albendazole is generally well toleratedin single-dose therapy for intestinal nematodes. The highdose,prolonged therapy required for clonorchiasis orechinococcal disease therapy can result in adverse effectssuch as bone marrow depression, elevation of hepatic enzymes,and alopecia.

Biochem/physiol Actions

Binds to tubulin and inhibits microtubule assembly.

Mechanism of action

Albendazole is given orally and is poorly and variably absorbed (5%) because of its poor water solubility. Oral bioavailability is increased as much as five times when the drug is given with a fatty meal instead of on an empty stomach. Concurrent treatment with corticosteroids increases plasma concentrations of albendazole. The drug is rapidly metabolized in the liver to an active sulfoxide metabolite.The half life of the metabolites is 8 to 12 hours.

Pharmacokinetics

Albendazole is a broad-spectrum anthelmintic. The principal mode of action for albendazole is by its inhibitory effect on tubulin polymerization which results in the loss of cytoplasmic microtubules.

Pharmacokinetics

Albendazole is better absorbed after oral absorption than other benzimidazole carbamates. It is extensively metabolized to the anthelmintically active albendazole sulfoxide, producing plasma concentrations of the metabolite of about 1.3 mg/L 2–5 h after a 400 mg oral dose. The half-life is about 8 h and the major route of excretion is via the bile. Plasma protein binding of the sulfoxide is around 70%.

Clinical Use

Albendazole has a broad spectrum of activity against intestinal nematodes and cestodes, as well as the liver flukes Opisthorchis sinensis, Opisthorchis viverrini, and Clonorchis sinensis. It also has been used successfully against Giardia lamblia. It is widely used throughout the world for the treatment of intestinalnematode infection. It is effective as a single-dose treatmentfor ascariasis, New and Old World hookworm infections,and trichuriasis. Multiple-dose therapy with albendazole caneradicate pinworm, threadworm, capillariasis, clonorchiasis,and hydatid disease. The effectiveness of albendazole againsttapeworms (cestodes) is generally more variable and lessimpressive. It also is effective in treating cerebral and spinal neurocysticercosis, particularly when given with dexamethasone.Albendazole is recommended for treatment of gnathostomiasis.

Side Effects

Various mild intestinal and other upsets usually resolve without treatment. With extended use, as for larval tapeworm infections, hepatic abnormalities or leukopenia may require discontinuation of treatment. In rare cases granulocytopenia, pancytopenia, agranulocytosis or thrombocytopenia may occur. It should not be given during pregnancy since it may cause fetal harm; women should be cautioned against becoming pregnant within a month of completing treatment.

Synthesis

Albendazole, methyl-[5-(propylthio)-1H-benzoimidazol-2-yl]carbamate (38.1.18), is also made by the heterocyclization of a derivative of phenylenediamine to a derivative of benzimidazole. In order to do that, 3-chloro-6-nitroacetanylide is reacted with propylmercaptane to make 3-propylthio-6-nitroacetanylide (38.1.6). Reducing the nitro group in this compound with hydrogen using a palladium on carbon catalyst gives 4-(propylthio)-o-phenylenediamine (38.1.7). Reacting the resulting derivative of o-phenylenediamine with cyanamide and then with the methyl chloroformate gives the desired albendazole.

Veterinary Drugs and Treatments

Albendazole is labeled for the following endoparasites of cattle (not lactating): Ostertagia ostertagi, Haemonchus spp., Trichostrongylus spp., Nematodius spp., Cooperia spp., Bunostomum phlebotomum, Oesphagostomum spp., Dictacaulus vivaparus (adult and 4th stage larva), Fasciola hepatica (adults), and Moniezia spp.
In sheep, albendazole is approved for treating the following endoparasites: Ostertagia circumcincta, Marshallagia marshalli, Haemonchus contortus, Trichostrongylus spp., Nematodius spp., Cooperia spp., Oesphagostomum spp., Chibertia ovina, Dictacaulus filaria, Fasciola hepatica, Fascioides magna, Moniezia expansa, and Thysanosoma actinoides.
Albendazole is also used (extra-label) in small mammals, goats and swine for endoparasite control.
In cats, albendazole has been used to treat Paragonimus kellicotti infections. In dogs and cats, albendazole has been used to treat capillariasis. In dogs, albendazole has been used to treat Filaroides infections. It has been used for treating giardia infections in small animals, but concerns about bone marrow toxicity have diminished enthusiasm for the drug’s use.

Metabolism

Hepatic. Rapidly converted in the liver to the primary metabolite, albendazole sulfoxide, which is further metabolized to albendazole sulfone and other primary oxidative metabolites that have been identified in human urine.