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 μM) and higher V max (15.8) than the liver (0.09 μM 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.