Title:Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs
Volume: 18
Issue: 1
Author(s): Xi He, Wenjun Hu, Fanhua Meng and Xingzhou Li*
Affiliation:
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850,China
Keywords:
Nitazoxanide, tizoxanide, prodrugs, plasma concentrations, first pass effect.
Abstract:
Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been
repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly
attributed to its metabolite−tizoxanide, the deacetylation product of nitazoxanide. In reference to the
pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations
and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant
first-pass effects in the liver. It was thought that this might be due to the unstable acyloxy bond
of nitazoxanide.
Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl
group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be
more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass
effect, which would improve plasma concentrations and system exposure of tizoxanide.
Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model
for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities.
Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide
(T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced
by the equimolar dosage of nitazoxanide. It was also found that the plasma concentration and
the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide.
Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide
prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the
active ingredient tizoxanide.
