Bioavailability and Metabolism of Mometasone Furoate following Administration by Metered‐Dose and Dry‐Powder Inhalers in Healthy Human Volunteers

Abstract

These studies were conducted to assess the systemic bioavailability of mometasone furoate (MF) administered by both the dry‐powder inhaler (DPI) and the metered‐dose inhaler with an alternate propellant (MDI‐AP). The pharmacokinetics of single doses (400 μg) of MF administered by intravenous (IV) and inhalation routes was assessed in a randomized, three‐way crossover study involving 24 healthy volunteers. In a separate study, 6 healthy subjects were administered a single dose of tritiated (3H‐) MF by DPI, and the radioactivity in blood, urine, feces, and expired air was determined. Following IV administration, MF was detected in all subjects for at least 8 hours postdose. The half‐life (t1/2) following IV administration was 4.5 hours. In contrast, following DPI administration, plasma MF concentrations were below the limit of quantification (LOQ, 50 pg/mL) for many subjects (10 of 24), and the systemic bioavailability by this route was estimated to be less than 1%. Only two plasma samples following MDI‐AP administration had plasma concentrations of MF above the LOQ, indicating no detectable systemic bioavailability in 92% of the subjects. A separate study with 6 healthy male subjects administered a single dose of3H‐MF (200 μCi) by DPI revealed that much of the dose (∼ 41%) was excreted unchanged in the feces (0–72 hours), while that which was absorbed was extensively metabolized. These results indicate that inhaled MF has negligible systemic bioavailability and is extensively metabolized and should therefore be well tolerated in the chronic treatment of asthma.

Sensitivity of Pharmacokinetics to Differences in the Particle Size Distribution for Formulations of Locally Acting Mometasone Furoate Suspension-Based Nasal Sprays

“…18 To block the confounding GI absorption and ensure that the detected plasma concentrations reflected the nasal absorption, a safe and effective oral dose of activated charcoal was administered in the present PK study. 5,16 Due to the gastrointestinal transit of charcoal, these charcoal doses were given within 5 min before and after the MF administration, with additional doses provided at 1, 2, and 3 h to maximize the impact of charcoal throughout the study.…”

“…The systemic bioavailability of intranasally administered drugs is the result of systemic absorption from the nasal cavity and from the GI tract, unless the latter is blocked. Single-dose administration of MF has previously been reported to have an oral bioavailability of approximately 1% due to extensive first-pass metabolism. , However, comparison of PK studies of nasally administered MF with and without charcoal to block the GI absorption showed that a significant fraction (approximately 50%) of the systemic MF exposure (AUC) was attributable to absorption from the GI tract, despite the low oral bioavailability. This may be explained as follows.…”

“…As the vast majority of the nasally deposited drug will reach the GI tract, even, if the oral bioavailability is small (about 1%,), approximately 50% of the total systemic exposure observed after Nasonex administration (i.e., the difference between 1.39 and 2.8%) is due to GI absorption . To block the confounding GI absorption and ensure that the detected plasma concentrations reflected the nasal absorption, a safe and effective oral dose of activated charcoal was administered in the present PK study. , Due to the gastrointestinal transit of charcoal, these charcoal doses were given within 5 min before and after the MF administration, with additional doses provided at 1, 2, and 3 h to maximize the impact of charcoal throughout the study.…”

Zein nanoparticles as oral carrier for mometasone furoate delivery

“…MF is a highly lipophilic compound with poor aqueous solubility developed for local administration and when administered by inhalation reveals low bioavailability, in which usually only less than 1% of the administered drug reaches the systemic circulation [ 6 ]. Moreover, a human pharmacokinetic study demonstrated that the half-life of MF following the intravenous route was 4.45 h, and MF was still detected in the bloodstream up to 8 h after administration [ 6 ]. The low availability that MF presents might be justified by its lipophilic character and the various obstacles, hindering the drug accessibility to the absorptive epithelium.…”

Nasal Absorption Enhancement of Mometasone Furoate Nanocrystal Dispersions

“…MF inhibits the arachidonic acid pathway, significantly suppressing the production of leukotrienes, inflammatory cytokines, and growth factors, and the expression of adhesion molecules. 8 MF is a lipophilic compound with low water solubility developed for topical administration, 9 and the absorbed drug is mainly excreted in bile as a metabolite and less frequently in urine. 9 In clinical settings, a nasal formulation of MF is commercially available as NASONEX nasal 50 µg/spray (traditional nasal MF formulations, CA-MF), a metered-dose pump spray with a pH of 4.3-4.9.…”