Table 2. Pharmacokinetic properties and side effects of benzimidazole anthelmintics.
| Drug | Dosage | Pharmocokinetic properties | Side effects | Ref. |
|---|---|---|---|---|
| Albendazole FDA approval (1996): category C | Human and veterinary use, 400 mg/day, p.o. and b.d. for 1 to 6 months in Echinococcus infection | Absorption: poor solubility and absorption (<5% in humans and 50% in cattle); increase up to 5 times when administered with a fatty meal | Common: headaches and hepatotoxicity with elevated liver enzymes | (5,99,100,101,102) |
| Distribution: widely distributed throughout the body including urine, bile, liver, cyst wall, cyst fluid, and CSF | Few: abdominal pain, nausea, vomiting, fever, and hypersensitivity reaction, such as hives and pruritus | |||
| Metabolism: Hepatic extensive first-pass effect; rapid sulfoxidation to active metabolite albendazole sulfoxide and finally inactive albendazole sulfone, hydrolysis, and oxidation | Rare: alopecia, telogen effluvium | |||
| Excretion: urine (<1% as active metabolite) and feces, hepatic clearance = 18.2 ml/min/kg | Other: leukopenia, anemia, thrombocytopenia, pancytopenia | |||
| Time to peak = 2–5 h for albendazole sulfoxide in serum | Avoid during pregnancy: teratogenic effects in the offspring of rats, but pregnant patients who received albendazole did not show an increased risk of teratogenicity | |||
| t1/2 = 8–12 h for albendazole sulfoxide | No risk of aneuploidy for conventional therapeutic use of albendazole in human | |||
| Protein binding = 70% | ||||
| Mebendazole approved in the United States in 1974 | Human and veterinary use | Absorption: poor solubility and absorption, 5%–10% in humans and 1%–2% after a high dose, enhanced by eating high-fat meals distribution: Vd = 1–2 L/kg | Anthelmintic spectrum and adverse effect profile of mebendazole is almost identical to albendazole | (5,101,103,104) |
| Some experts recommend: 200 to 400 mg, p.o. and t.i.d. for 3 days, then 400 to 500 mg, p.o. and t.i.d. for 10 days for trichinosis | Metabolism: extensively hepatic first pass metabolism involving keto-reduction and decarbamylation, followed by conjugation | Relatively non-toxic, well-tolerated | ||
| Excretion: primarily feces (as unchanged drug and primary metabolite) and urine (<2%) | Side effects are uncommon with rare cases, such as gastrointestinal upset, fever, diarrhea, abdominal pain, discomfort, flatulence, diarrhea, hypersensitivity reactions, such as rash, urticaria, and angioedema | |||
| t1/2 = 3–6 h | High doses may induce anemia and hepatotoxicity with rare instances of neutropenia, marrow aplasia, alopecia | |||
| Protein Binding = 90%–95% | Rodents showed fetal toxicity and teratogenicity at high doses, but not other species including rabbits, horses, sheep, and swine | |||
| Pass through the blood–brain barrier | Contraindicated for pregnancy | |||
| Aneuploidy in in vitro and in vivo experiments but not considered to be a risk to humans receiving conventional therapy | ||||
| Fenbendazole | Veterinary use | Metabolism: extensively hepatic first pass to the active metabolite fenbendazole sulfoxide (active form) and finally fenbendazole sulfone | A nontoxic drug in rodents: LD50 exceeds 10 g/kg (a dose 1,000 times the therapeutic level) | (105,106) |
| Excretion: primarily feces and urine | Lifetime studies in rats: lack of carcinogenesis, no maternal and reproductive toxicity | |||
| Morphologic changes of hepatocellular hypertrophy and hyperplasia in rats | ||||
| No observed adverse effect in mice | ||||
| Myelosuppression in dogs and birds, but not in rodents | ||||
| Ricobendazole (albendazole sulfoxide) | Absorption: poor bioavailability and enhanced hydrosolubility | Ricobendazole is a key metabolite of albendazole; may have side effects similar to albendazole | (5,105) | |
| Vd = 0.67–1.2 L/kg in cattle and sheep | ||||
| Metabolism: absorbed oxfendazole is partly and reversibly reduced to albendazole both in the liver and in the rumen | ||||
| Excretion: feces and urine | ||||
| t1/2 = 8–12 h in man | ||||
| Protein binding = 70% | ||||
| Crosses the blood–brain barrier | ||||
| Ricobendazole enantiomers have a species difference in pharmacokinetic profiles | ||||
| Oxfendazole (fenbendazole sulfoxide) | Veterinary use | Enhanced hydrosolubility | Well-tolerated in most species | (105,107) |
| Distribution throughout the body | Main symptoms of intoxication after high oral doses: loss of appetite, diarrhea, fever, cramps, nausea, vomit and convulsions | |||
| Metabolism: absorbed oxfendazole is partly and reversibly reduced to fenbendazole both in the liver and in the rumen | Hepatic and epicardial hemorraghe can also happen | |||
| Excretion: 80% through bile and feces in ruminants | Mutagenic effects, embryotoxicity, teratogenicity in mice | |||
| t1/2 = 8–12 h in human (NCT03035760, NCT02234570) | ||||
| Oxfendazole enantiomers have a species difference in pharmacokinetic profiles | ||||
| Flubendazole | Veterinary use | Absorption: poor bioavailability | Well-tolerated without adverse effects | (108) |
| Metabolism: extensive first pass via carbamate hydrolysis and ketone reduction to inactive metabolites | Not be used in pregnant or lactating queens, nor in puppies younger than 1 year | |||
| Excretion: more than 80% of p.o. dose in feces and only very small amounts of unchanged drug (less than 0.1%) in the urine | ||||
| t1/2 in tissues = 1–2 days | ||||
| Oxibendazole | Veterinary use | Absorption: poor bioavailability but increased bioavailabiblity in sheep and goats splitting the therapeutic dose during 3 consecutive days (each day 1/3 of the recommended dose) | Well-tolerated in most species | (109) |
| Metabolism: little information but expected broken down in the liver to metabolites without anthelmintic activity | No acute toxicity with single oral doses in mice (4–32 g/kg of body weight), sheep (230–600 mg/kg), and cattle (600 mg/kg) | |||
| No subacute toxicity with multiple doses for 5 days in cattle (30–75 mg/kg/day) and sheep (10–50 mg/kg/day) | ||||
| No chronic effects with 3–30 mg/kg for 98 days in rats and dogs | ||||
| No teratogenicity in mice, rats, sheep at 30 mg/kg and cattle at 75 mg/kg during pregnancy | ||||
| Main symptoms after high oral doses: vomiting, depression, trembling | ||||
| Parbendazole | Veterinary use | Peak blood levels = 6–8 h after administration | Pregnant animals are contraindicated: teratogenicity is largely skeletal | (110) |
| Laxation (soft dung/diarrhea), anorexia, listlessness |
LD50, lethal dose, 50%; p.o., oral administration; t1/2, half-life time; t.i.d., three times a day; Vd, volume of distribution.