Metabolism and Disposition of Tribendimidine and Its Metabolites in Healthy Chinese Volunteers

Abstract

Background: Tribendimidine is a new anthelmintic agent synthesized by Chinese scientists. It is a broad spectrum agent with high activity against parasites. However, its disposition and metabolism remain unknown.Objective: To investigate the metabolism, disposition, and metabolites of tribendimidine in healthy human volunteers.Methods: Twelve healthy Chinese volunteers were chosen after clinical assessment of health status and laboratory tests. They received single oral doses of tribendimidine 400mg enteric-coated tablets. Blood and urine samples were collected at scheduled timepoints. Samples were qualitatively and quantitatively analyzed by liquid chromatography-mass spectrometric (LC-MS) and high performance liquid chromatography (HPLC) methods, respectively.Results: Tribendimidine was rapidly and completely broken down to p-(1-dimethylamino ethylimino) aniline (dADT) and terephthalaldehyde (TPAL). Furthermore, dADT was partially transformed to acetylated dADT, and TPAL completely transformed to terephalic acid (TPAC). The main pharmacokinetic parameters (± SD) of dADT were as follows: elimination half life (t1/2) 4.74 ± 1.80 h; elimination rate constant (Ke) 0.16 ± 0.06 h−1; apparent volume of distribution (Vd/F) 12.23 ± 8.69L • kg−1; apparent total clearance of the drug from plasma (CL/F) 1.63 ± 0.58L • h−1 • kg−1; area under the plasma concentration-time curve (AUC) from time 0 to time 24 hours (AUC24) 4.29 ± 1.88 μg • mL−1 • h; AUC from time zero to infinity (AUC∞) 4.45 ± 1.81 μg • mL−1 • h; maximum plasma drug concentration (Cmax) 0.64 ± 0.27 μg • mL−1; and time to Cmax (tmax) 4.20 ± 0.71 h. A total of 35.28% dADT and 28.50% TPAC were excreted through the urine within 24 hours after tribendimidine administration.Conclusion: These results reveal the disposition, metabolism, and main metabolites of tribendimidine in healthy Chinese volunteers.

The effect of tribendimidine and its metabolites against Necator americanus in golden hamsters and Nippostrongylus braziliensis in rats

“…2 The ED 1 -ED 95 curve of tribendimidine (TBD) and its metabolites and dADT in treatment of rats infected with Nippostrongylus braziliensis aforementioned that AdADT has been degraded in the stomach of the rat before the drug reaches to the small intestine. According to the pharmacokinetic data of TBD, dADT is a major metabolite present in the blood and urine after oral administration of TBD, while the secondary metabolite of AdADT is found in the urine (Yuan et al 2008b). Therefore, it is suggested that in treatment of intestinal nematodes, TBD and dADT display the major role, and in treatment of C. sinensis, dADT is the major effective metabolites.…”

“…In a clinical trial undertaken in 1980, the results showed that amidantel possessed higher efficacy against A. lumbricoides and Ancylostoma duodenale infection in humans, but none of the patients with N. americanus was cured by the drug (Rim et al 1980). Apart from plasma, dADT was also found in urine by high-performance liquid chromatography method (Yuan et al 2008b). Interestingly, dADT may proceed the secondary metabolism which results in formation of acetylated dADT (AdADT) detected in urine (Yuan et al 2008b).…”

“…Apart from plasma, dADT was also found in urine by high-performance liquid chromatography method (Yuan et al 2008b). Interestingly, dADT may proceed the secondary metabolism which results in formation of acetylated dADT (AdADT) detected in urine (Yuan et al 2008b). Theoretically, one molecule of TBD can be degraded into two molecules of dADT and one molecule of terephthalaldehyde (TPAL).…”

The in vitro and in vivo effect of tribendimidine and its metabolites against Clonorchis sinensis

“…Meanwhile, dADT is further metabolized to AdADT ( Fig. 1d; Yuan et al 2008b) and its chemical structure is similar to that of ADT. Since adult C. sinensis parasitize in the liver bile duct system, the oral drug displays its effect against the worms only after it is absorbed from the intestinal tract.…”

“…1c; Tomlinson et al 1985;Yuan et al 2008a) and its secondary metabolite, acetylated dADT (AdADT; Fig. 1d), were detected in the urine (Yuan et al 2008b). Although the predict metabolite, terephthaldehyde (TPAL; Fig.…”