Pharmacology
editMechanism of Action
editBenznidazole is a nitroimidazole antiparasitic with good activity against acute infection with Trypansoma cruzi, commonly referred to as Chagas Disease.[1] Like other nitroimidazoles, benznidazole's main mechanism of action is to generate radical species which can damage the parasite's cellular machinery.[2] The mechanism by which nitroimidazoles do this seems to depend on whether or not oxygen is present.[3] This is particularly relevant in the case of Trypanosoma species, which are considered facultative anaerobes.[4]
Under anaerobic conditions, the nitro group of nitroimidazoles is believed to be reduced by the pyruvate:ferredoxin oxidoreductase complex to create a reactive nitro radical species.[2] The nitro radical can then either engage in other redox reactions directly or spontaneously give rise to a nitrite ion and imidazole radical instead.[3] The initial reduction takes place because nitroimidazoles are better electron acceptors for ferredoxin than the natural substrates.[2] In mammals, the principal mediators of electron transport are NAD+/NADH and NADP+/NADPH, which have a more positive reduction potential and so will not reduce nitroimidazoles to the radical form.[2] This limits the spectrum of activity of nitroimidazoles so that host cells and DNA are not also damaged. This mechanism has been well-established for 5-nitroimidazoles such as metronidazole, but it is unclear if the same mechanism can be expanded to 2-nitroimidazoles (including benznidazole).[3]
In the presence of oxygen, by contrast, any radical nitro compounds produced will be rapidly oxidized by molecular oxygen, yielding the original nitroimidazole compound and a superoxide anion in a process known as "futile cycling".[2] In these cases, the generation of superoxide is believed to give rise to other reactive oxygen species.[3] The degree of toxicity or mutagenicity produced by these oxygen radicals depends on cells' ability to detoxify superoxide radicals and other reactive oxygen species.[3] In mammals, these radicals can be converted safely to hydrogen peroxide, meaning benznidazole has very limited toxicity to human cells.[3] In Trypansoma species, however, there is a reduced capacity to detoxify these radicals, which results in damage to the parasite's cellular machinery.[3]
Pharmacokinetics
editOral benznidazole has a bioavailability of 92%, with a peak concentration time of 3-4 hours after administration.[5] 5% of the parent drug is excreted unchanged in the urine, which implies that clearance of benznidazole is mainly through metabolism by the liver.[6] Its elimination half-life is 10.5-13.6 hours.[5]
Interactions
editBenznidazole and other nitroimidazoles have been shown to decrease the rate of clearance of 5-fluorouracil (including 5-fluorouracil produced from its prodrugs capecitabine, doxifluridine, and tegafur).[5] While co-administration of any of these drugs with benznidazole is not contraindicated, monitoring for 5-fluorouracil toxicity is recommended in the event they are used together.[5]
The GLP-1 receptor agonist lixisenatide may slow down the absorption and activity of benznidazole, presumably due to delayed gastric emptying.[5]
Because nitroimidazoles can kill Vibrio cholerae cells, use is not recommended within 14 days of receiving a live cholera vaccine.[5]
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- ^ Pérez-Molina, José A.; Pérez-Ayala, Ana; Moreno, Santiago; Fernández-González, M. Carmen; Zamora, Javier; López-Velez, Rogelio (2009-12-01). "Use of benznidazole to treat chronic Chagas' disease: a systematic review with a meta-analysis". Journal of Antimicrobial Chemotherapy. 64 (6): 1139–1147. doi:10.1093/jac/dkp357. ISSN 0305-7453. PMID 19819909.
- ^ a b c d e Edwards, David I. "Nitroimidazole drugs - action and resistance mechanisms. I. Mechanism of action" Journal of Antimicrobial Chemotherapy 1993, volume 31, pp. 9-20. doi:10.1093/jac/31.1.9.
- ^ a b c d e f g Eller, Gernot. "Scientia Pharmaceutica". doi:10.3797/scipharm.0907-14.
{{cite journal}}: Cite journal requires|journal=(help) - ^ Cheng, Thomas C. (1986). General Parasitology. Orlando, Florida: Academic Press. p. 140. ISBN 0-12-170755-5.
- ^ a b c d e f "Benznidazole". Micromedex. Truven Health Analytics. Retrieved November 5, 2016.
- ^ Workman, P.; White, R. A.; Walton, M. I.; Owen, L. N.; Twentyman, P. R. (1984-09-01). "Preclinical pharmacokinetics of benznidazole". British Journal of Cancer. 50 (3): 291–303. ISSN 0007-0920. PMC 1976805. PMID 6466543.