Effect of nitazoxanide on albendazole pharmacokinetics in cerebrospinal fluid and plasma in rats

Abstract

Although albendazole is the drug-of-choice for the treatment of neurocysticercosis, its efficacy is limited due to its low bioavailability. An alternative for optimizing pharmacological treatment is through drug combinations. studies have shown that nitazoxanide and tizoxanide (the active metabolite of nitazoxanide) exhibit cysticidal activity and that the combination of tizoxanide with albendazole sulfoxide (the active metabolite of albendazole) produced an additive effect. (1) To assess the concentration profile of tizoxanide in plasma and in cerebrospinal fluid; and (2) to evaluate the influence of nitazoxanide on the pharmacokinetics of albendazole in plasma and in cerebrospinal fluid. Two different studies were conducted. In study 1, 10 male Sprague-Dawley rats received a single oral dose of 7.5 mg/kg of nitazoxanide and serial blood and cerebrospinal fluid samples were collected over a period of 4 h. In study 2, 38 healthy male Sprague-Dawley rats were randomly divided into two groups: one of these received a single dose of albendazole (15 mg/kg) and, in the other group, albendazole (15 mg/kg) was co-administered with nitazoxanide (7.5 mg/kg). Plasma and cerebrospinal fluid samples were collected from 0 to 16 h after administration. Albendazole sulfoxide and tizoxanide levels were assayed by using HPLC or LC/MS techniques. In study 1, tizoxanide reached a maximum plasma concentration of 244.42 ± 31.98 ng/mL at 0.25 h; however, in cerebrospinal fluid, this could be detected only at 0.5 h, and levels were below the quantification limit (10 ng/mL). These data indicate low permeation of tizoxanide into the blood brain barrier. In study 2, Cmax, the area under the curve, and the mean residence time of albendazole sulfoxide in plasma and cerebrospinal fluid were not affected by co-administration with nitazoxanide. The results of the present study indicate that in rats at the applied doses, tizoxanide does not permeate into the cerebrospinal fluid. Furthermore, nitazoxanide does not appear to alter significantly the pharmacokinetics of albendazole in plasma or in cerebrospinal fluid.

Pharmaceutical cocrystals: walking the talk

“…102 NTZ has poor aqueous solubility (7.55 mg mL À1 in water) and even lower bioavailability (258 ng mL À1 , 7.5 mg kg À1 dose in rats). 103 Two isomorphous cocrystals (drug-drug pharmaceuticals) of NTZ with PASA and PABA (p-aminosalicylic acid and p-aminobenzoic acid in a 1 : 1 stoichiometry) as well as solid solutions of cocrystal alloys NTZÀPABA :NTZÀPASA with 0.75 : 0.25 (CA2) and 0.67 : 0.33 (CA1) compositions were prepared by grinding and solution crystallization (see the scheme in Fig. 35a).…”

A fusion peptide in preS1 and the human protein disulfide isomerase ERp57 are involved in hepatitis B virus membrane fusion process

“…Importantly, we showed that a short-time treatment of liver humanized mice with NTZ could delay HBV infection by approximately 2–4 weeks ( Figure 9 ). Since NTZ has a short half-life of about 1.5 hr in vivo ( Ruiz-Olmedo et al, 2017 ; Stockis et al, 1996 ) and since NTZ was administrated at very short times before and after HBV inoculation, we calculated that less than 10% of the drug was still present in those mice at 7 hr post-infection, which likely precludes an effect on HBV post-entry steps ( Korba et al, 2008 ). Altogether, these results support the role of ERp57 at early steps of HBV infection and validate this PDI as a therapeutic target.…”

“…Finally, we sought to demonstrate that ERp57 inhibition may prevent HBV propagation in vivo using NTZ, which has a short half-life of about 1.5h (Ruiz-Olmedo et al, 2017;Stockis et al, 1996). We generated a cohort of liver humanized mice (HuHep-mice) derived from the NFRG mouse model (Azuma et al, 2007) (Figure 9A).…”

Cocrystals and alloys of nitazoxanide: enhanced pharmacokinetics

“…12 NTZ has poor aqueous solubility (7.55 mg mL À1 in water) 13 and even lower bioavailability (258 ng mL À1 , 7.5 mg kg À1 dose in rats). 14 A Cambridge Structural Database search of NTZ gave four hits, of which one is a guest free form and three are cocrystals. 15,16 We report two isomorphous cocrystals (drug-drug pharmaceuticals) of NTZ with PASA and PABA (1 : 1 stoichiometry) as well as solid solutions of cocrystal alloys NTZ-PABA : NTZ-PASA of 0.75 : 0.25 and 0.67 : 0.33 composition.…”