Enhancing Oral Bioavailability of Methylnaltrexone Using an Emulsion Formulation

Methylnaltrexone (MNTX) is a peripherally-acting opioid receptor antagonist. Since it has restricted access to the blood-brain barrier, MNTX has the ability to decrease opioid-induced constipation without affecting the analgesic effects of opioid pain medications. MNTX has a limited gastrointestinal absorption and currently, only subcutaneous MNTX is clinically available to help restore bowel function in patients with late-stage advanced illness who are receiving opioids. A MNTX emulsion (MNTX-EM) formulation was prepared in this study to improve the oral bioavailability of the compound. A sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was established and validated for the determination of MNTX plasma concentrations. With an extended linear range of 1 to 1000 ng/mL, this assay was specific, precise, and accurate. Following 110 mg/kg oral administrations of unformulated methylnaltrexone water solution (MNTX-WS) and MNTX-EM in rats, plasma samples were collected for up to 9 h and MNTX levels were measured. The plasma MNTX concentrations after MNTX-WS and MNTX-EM were compared. Data showed that there were two MNTX concentration peaks after both MNTX-WS and MNTX-EM. For the first peak, the peak plasma concentration (Cmax) and the area under the concentration curve (AUC) from 0 to 60 min for MNTX-WS and MNTX-EM were 210.0 ng/mL, 87.2 ng•h/mL and 390.2 ng/mL, 321.9 ng•h/mL, respectively (both P < 0.01). For the second peak, Cmax and AUC from 60 to 420 min for MNTX-WS and MNTX-EM were 172.7 ng/mL, 663.4 ng•h/mL and 597.6 ng/mL, 1941.7 ng•h/mL, respectively (both P < 0.01). The relative bioavailability after oral administration of MNTX-EM was 302% compared to that of MNTX-WS. These results suggested that the emulsion formulation might be clinically useful in enhancing the oral absorption of MNTX.