Pharmacokinetics, Metabolism and Excretion of Megazol, a New Potent Trypanocidal Drug in Animals

Abstract

The pharmacokinetics of megazol (CAS 19622-55-0) was investigated after intraperitoneal and oral administration of the drug (80 mg/kg) to mice. The plasma levels were significantly higher after oral administration of drug than after intraperitoneal route (33.8 micrograms/ml compared with 19.0 micrograms/ml for Cmax, 158714 micrograms.h/l compared with 96057 micrograms.h/l for AUC). When suramin (CAS 145-63-1) was administered 24 h before oral administration of megazol, megazol absorption was accelerated (2 h compared with 4 h for Tmax) but the amount absorbed was lower (19.9 micrograms/ml compared with 33.8 micrograms/ml for Cmax and 95547 micrograms.h/l vs 158714 micrograms.h/l for AUC). In the infected mice previously treated with suramin, all estimated pharmacokinetic parameters of plasma megazol were significantly modified, in particularly an increase in the apparent volume of distribution (5.6 l/kg compared with 0.9 l/kg) with a prolongation of the elimination half-life (3 h compared with 0.7 h) of megazol. Excretion of the total radioactivity of megazol was also evaluated after oral administration of 3H-megazol to rats. Total radioactivity was eliminated predominantly via the urinary route (80%) vs. 10.5% in the faeces, 9.5% remaining in the body 8 days after dosing. When unlabelled megazol was orally administered to rats with absence or presence of suramin, megazol recovered in urine and faeces 72 h dosing was: 55.7%/2% vs 20.6%/1.6%, respectively. In the urine, unchanged megazol was present as characterized by LC-MS/MS as well as 4 unknown metabolites. This study indicates that suramin significantly affects the pharmacokinetics of megazol and its elimination.

Pharmacokinetics, Metabolism and Excretion of Megazol in a Trypanosoma brucei gambiense Primate Model of Human African Trypanosomiasis

“…Moreover, the product ion spectrum obtained from the selected MH + parent ion displayed main diagnostic fragment ions which can be interpreted as follows: m/z 210 (MH-NH 3 ) + , m/ z 197 (MH-NO) + , m/z 181 (MH-NO 2 ) + . This spectrum was superimposable with the spectrum obtained from standard megazol under the same experimental conditions, thus confirming that in primate, megazol was excreted in unchanged form as well as in rat (Enanga et al, 1999). On the other hand, the metabolites contained in acidic extract were tentatively characterized using LC-ESI-MS/MS on the basis of their protonated molecular ions.…”

“…We are currently carrying out a study in vitro of the intestinal absorption of megazol using the everted sac model. The metabolic profile of megazol in the infected primate was similar to the profile in uninfected rat (Enanga et al 1999). Quantitatively, M1 and M2 were more in the primate than in rat.…”

“…Determination of MIC 100 of T. b. gambiense is necessary for optimization of the treatment, because, according to Nau et al (1998), a drug concentration of at least 10 times minimal inhibitory concentration is required to rapidly rid cerebrospinal fluid of parasites. For the animals with prolonged infection, an acceleration of megazol absorption in the gastrointestinal tract was observed compared with shortterm infections as previously described in mouse (Enanga et al 1999). The elimination half-life of megazol, which ranged from 2.7 h to 2.89 h, was considerably shorter than other 5-nitroimidazole compounds, such as metronidazole (7−8 h), tinidazole (12−13 h), ornidazole (13 h) and secnidazole (17−29 h) in human (André 1979).…”

Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme

“…When screened on trypanosomes, it was shown to be more effective against T. cruzi than compounds 1 or 2, displaying activity towards strains that were refractory to these two nitroheterocycles (Filardi & Brener 1987). It also displayed considerable growth inhibitory activity against T. brucei , in which it was demonstrated to promote parasite clearance in animals after the administration of a single dose (Bouteille et al 1995, Enanga et al 1999, 2000). …”

Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950–2021 Comprehensive Overview

“…Megazol 15 has also shown activity against Human African trypanosomiasis (HAT) or sleeping sickness with in vitro activity against T. b. brucei with an EC 50 of 0.01 µg/mL and was found to be effective in curing the acute disease condition ( Figure 19 ) [ 144 ]. Megazol 15 has good oral exposure with the highest AUC and C max values when compared to the intraperitoneal route [ 145 ].…”