Contributions of Hepatic and Intestinal Metabolism to the Disposition of Niclosamide, a Repurposed Drug with Poor Bioavailability

Abstract

Niclosamide, an antiparasitic, has been repositioned as a potential therapeutic drug for systemic diseases based on its antiviral, anticancer, and anti-infection properties. However, low bioavailability limits its in vivo efficacy. Our aim was to determine whether metabolic disposition by microsomal P450 enzymes in liver and intestine influences niclosamide's bioavailability in vivo, by comparing niclosamide metabolism in wild-type, liver-Cpr-null (LCN), and intestinal epithelium-Cpr-null (IECN) mice. In vitro stability of niclosamide in microsomal incubations was greater in the intestine than in liver in the presence of NADPH, but it was much greater in liver than in intestine in the presence of UDPGA. NADPH-dependent niclosamide metabolism and hydroxy-niclosamide formation were inhibited in hepatic microsomes of LCN mice, but not IECN mice, compared with wild-type mice. In intestinal microsomal reactions, hydroxy-niclosamide formation was not detected, but rates of niclosamide-glucuronide formation were ∼10-fold greater than in liver, in wild-type, LCN, and IECN mice. Apparent Km and V max values for microsomal niclosamide-glucuronide formation showed large differences between the two tissues, with the intestine having higher Km (0.47 mM) and higher V max (15.8) than the liver (0.09 mM and 0.75, respectively). In vivo studies in LCN mice confirmed the essential role of hepatic P450 in hydroxy-niclosamide formation; however, pharmacokinetic profiles of oral niclosamide were only minimally changed in LCN mice, compared with wild-type mice, and the changes seem to reflect the compensatory increase in hepatic UDP-glucuronosyltransferase activity. SIGNIFICANCE STATEMENT These results suggest that efforts to increase the bioavailability of niclosamide by blocking its metabolism by P450 enzymes will unlikely be fruitful. In contrast, inhibition of niclosamide glucuronidation in both liver and intestine may prove effective for increasing niclosamide's bioavailability, thereby making it practical to repurpose this drug for treating systemic diseases.

JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both In Vitro and In Vivo

“…27 Moreover, niclosamide was found as a broad-spectrum antiviral against multiple viruses including SARS Cov-2, the causative agent of the current COVID-19 pandemic. 28 Unfortunately, niclosamide did not show appreciable in vivo antiviral efficacy toward ZIKV (data not shown), possibly due to its poor pharmacokinetic properties 26,29 In this work, we screened a small library of niclosamide derivatives. We found that one derivative, JMX0207, showed improved efficacy in the inhibition of the NS2B-NS3 interaction, better inhibition of viral protease function, and enhanced antiviral efficacy in the cell-based antiviral assay, compared to niclosamide.…”

Niclosamide Inhalation Powder Made by Thin-Film Freezing: Pharmacokinetic and Toxicology Studies in Rats and Hamsters

“…So, the results of niclosamide inhalation powder and those concentrations above the limit of quantification support the idea of once-daily administration. This may be attributed to an extended residence time in the lung resulting from the avoidance of the extensive first-pass effect that niclosamide undergoes after oral administration [37]. Despite the fact that some drug remains in the plasma, it is reasonable that niclosamide does not accumulate in the lungs following three consecutive days of daily dosing as supported by the low concentrations measured in the lung tissue (Table 4).…”

Niclosamide encapsulated in mesoporous silica and geopolymer: A potential oral formulation for COVID-19

“…In addition, viral replication can be inhibited by NIC, preventing their further maturation in the host cells [ 19 ]. However, NIC can undergo faster metabolism in liver as glucuronic acid-NIC metabolite by cytochrome P450 enzymes [ 20 ]. Therefore, it is required to have drug delivery carrier to release encapsulated NIC molecules in a sustained manner to delay the metabolism by glucuronidation in liver and/or intestine in a tricky way.…”