Mebendazole

In vitro and in vivo work suggests that mebendazole blocks the uptake of glucose by adult and larval forms of helminths, in a selective and irreversible manner. Inhibition of glucose uptake appears to lead to endogenous depletion of glycogen stores within the helminth. Lack of glycogen leads to decreased formation of ATP and ultrastructural changes in the cells.

There is no evidence that mebendazole is effective in the treatment of cysticercosis.

Absorption

Following oral administration, <10% of the dose reaches the systemic circulation, due to incomplete absorption and pre-systemic metabolism (first-pass effect). The majority of an orally administered dose remains in the gastrointestinal tract. Maximum plasma concentrations are generally seen 2 to 4 hours after administration. Administration with a high fat meal increases the bioavailability of mebendazole, but the overall effect of food on the amount of drug remaining in the gastrointestinal tract is not expected to be substantial.

Distribution

The plasma protein binding of mebendazole is 90 to 95%. The volume of distribution is 1 to 2 L/kg, indicating that mebendazole penetrates areas outside the vascular space. This is supported by data in patients on chronic mebendazole therapy (e.g. 40 mg/kg/day for 3-21 months) that show drug levels in tissue.

Metabolism

Orally administered mebendazole is extensively metabolised primarily by the liver. Plasma concentrations of its major metabolites (hydrolysed and reduced forms of mebendazole) are substantially higher than those of mebendazole. Impaired hepatic function, impaired metabolism, or impaired biliary elimination may lead to higher plasma levels of mebendazole.

Elimination

Mebendazole, the conjugated forms of mebendazole, and its metabolites likely undergo some degree of enterohepatic recirculation and are excreted in the urine and bile. The apparent elimination half-life after an oral dose ranges from 3 to 6 hours in most patients.

Steady-state pharmacokinetics

During chronic dosing (e.g. 40 mg/kg/day for 3-21 months), plasma concentrations of mebendazole and its major metabolites increase, resulting in approximately 3-fold higher exposure at steady-state compared to single dosing.

Paediatric population

Limited data of the mebendazole concentrations in plasma are available in children and adolescents 1 to 16 years of age. These data do not indicate substantially higher systemic exposure to mebendazole in subjects 3 to 16 years of age compared to adults.

In subjects 1 to <3 years of age, systemic exposure is higher than in adults due to higher mg/kg dose relative to adults.

In animal reproduction studies, adverse developmental effects (i.e. skeletal malformations, soft tissue malformations, decreased pup weight, embryolethality) were observed when mebendazole was administered to pregnant rats and mice throughout the period of organogenesis or as a single oral dose as low as 10 mg/kg in rats (approximately 0.2-fold the maximum recommended human dose (MRHD)). Maternal toxicity was present at the highest of these doses. Dosing of hamsters and rabbits did not result in embryotoxicity or teratogenicity. Doses up to 40 mg/kg in rats (0.8-fold the MRHD, based on mg/m²), given to males for 60 days and to females for 14 days prior to gestation, had no effect upon fetuses and offspring.

No mutagenic activity was observed with mebendazole in bacterial reverse mutation tests. Mebendazole was mutagenic when tested in the mouse lymphoma thymidine kinase assay and aneugenic in vitro in mammalian somatic cells. In the in vivo mouse micronucleus assay, orally administered mebendazole induced an increased frequency of micronucleated polychromatic erythrocytes with evidence suggestive of aneugenicity.

Mebendazole had no carcinogenic effects at doses as high as 40 mg/kg/day when administered daily in the diet over 2 years in carcinogenicity tests in mice and rats (0.4 to 0.8-fold the MRHD, based on mg/m²).