A combined in vitro in-silico approach to predict the oral bioavailability of borderline BCS Class II/IV weak base albendazole and its main metabolite albendazole sulfoxide

Pettarin, Maximo; Bolger, Michael B.; Chronowska, Maja; Kostewicz, Edmund

doi:10.1016/j.ejps.2020.105552

Cited by 10 publications

(13 citation statements)

References 53 publications

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“…In the case of ABZ-Doc, an additional endothermic event was noted at around ∼150 °C, which could be indicative of the recrystallization of the ABZ form II. Previous reports show the generation of ABZ form II when methanol is used for recrystallization . As we used methanol for the synthesis of our docusate-based ILs, we believe that the ABZ form II may have been generated.…”

Section: Resultssupporting

confidence: 71%

“…In the case of ABZ-Doc, an additional endothermic event was noted at around ∼150 °C, which Previous reports show the generation of ABZ form II when methanol is used for recrystallization. 20 As we used methanol for the synthesis of our docusate-based ILs, we believe that the ABZ form II may have been generated. Powder X-ray diffractograms (XRDs) of pure ABZ, MBZ, FBZ, sodium docusate, and the docusate-based ILs are shown in Figure 5.…”

Section: ■ Resultsmentioning

confidence: 99%

“…As expected, the anthelmintic benzimidazoles had 17- to 130-fold higher solubility in pH 1.2 buffer compared to water (Table ), confirming the pH-dependent solubility of these compounds reported in the literature. , In contrast, the docusate-based ILs showed low solubility in both pH 1.2 buffer and water (Table ), indicating their pH-independent behavior. Thus, the association of the amphiphilic docusate anion with the benzimidazole ring resulted in the abolishment of the pH-dependent solubility.…”

Section: Resultsmentioning

confidence: 99%

“…43 A recent study also suggests that ABZ has poor gastrointestinal permeability. 20 The suboptimal physicochemical and biopharmaceutical properties of anthelmintic benzimidazoles result in low and variable oral bioavailability. For example, the oral bioavailability of ABZ from currently available tablets is ∼5%, 47 whereas MBZ oral bioavailability in humans ranges from 12% to 35%.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Previous studies showed that ABZ, MBZ, and FBZ are active against C. neoformans in vitro , and FBZ was active against fluconazole-resistant C. neoformans . ,− Thus, anthelmintic benzimidazoles have the potential to be repurposed for the treatment of CM. However, these compounds have a high polymorphic tendency and extremely low and pH-dependent solubility, which result in low and variable oral bioavailability. − Additionally, due to their high crystallinity, anthelmintic benzimidazoles have poor solubility in commonly used organic solvents that affect their pharmaceutical processability and the utility of commonly used solubility enhancement approaches. It is noteworthy that FBZ, despite its potent in vitro activity, failed to show any efficacy in a murine model of CM when administered as an oral suspension .…”

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confidence: 99%

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Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and in Vitro Activity against Cryptococcus neoformans

et al. 2021

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As the existing therapeutic modalities for the treatment of cryptococcal meningitis (CM) have suboptimal efficacy, repurposing existing drugs for the treatment of CM is of great interest. The FDA-approved anthelmintic benzimidazoles, albendazole, mebendazole, and flubendazole, have demonstrated potent but variable in vitro activity against Cryptococcus neoformans, the predominant fungal species responsible for CM. We performed molecular docking studies to ascertain the interaction of albendazole, mebendazole, and flubendazole with a C. neoformans β-tubulin structure, which revealed differential binding interactions and explained the different in vitro efficacies reported previously and observed in this investigation. Despite their promising in vitro efficacy, the repurposing of anthelmintic benzimidazoles for oral CM therapy is significantly hampered due to their high crystallinity, poor pharmaceutical processability, low and pH-dependent solubility, and drug precipitation upon entering the intestine, all of which result in low and variable oral bioavailability. Here, we demonstrate that the anthelmintic benzimidazoles can be transformed into partially amorphous low-melting ionic liquids (ILs) with a simple metathesis reaction using amphiphilic sodium docusate as a counterion. In vitro efficacy studies on a laboratory reference and a clinical isolate of C. neoformans showed 2-to 4-fold lower IC 90 values for docusate-based ILs compared to the pure anthelmintic benzimidazoles. Furthermore, using a C. neoformans strain with green fluorescent protein (GFP)-tagged β-tubulin and albendazole and its docusate IL as model candidates, we showed that the benzimidazoles and their ILs reduce the viability of C. neoformans by interfering with its microtubule assembly. Unlike pure anthelmintic benzimidazoles, the docusate-based ILs showed excellent solubility in organic solvents and >30-fold higher solubility in bioavailability-enhancing lipid vehicles. Finally, the docusate ILs were successfully incorporated into SoluPlus, a self-assembling biodegradable polymer, which upon dilution with water formed polymeric micelles with a size of <100 nm. Thus, the development of docusate-based ILs represents an effective approach to improve the physicochemical properties and potency of anthelmintic benzimidazoles to facilitate their repurposing and preclinical development for CM therapy.

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Section: Resultssupporting

confidence: 71%

Section: ■ Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%