Disposition and metabolism of indeloxazine hydrochloride, a cerebral activator, in rats

Abstract

1. The disposition and metabolism of indeloxazine hydrochloride ((+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride) were studied in male Sprague-Dawley rats. 2. After oral administration of 14C-indeloxazine hydrochloride, the plasma concentration of total radioactivity reached a maximum at 15 min and declined with an apparent half-life of 2.2 h in the first 6 h period and declined more slowly thereafter. Unchanged drug in the plasma represented 13.5%, 5.9% and 0.4% of the total radioactivity at 15 min, 1 h and 6 h respectively after administration and levels decayed with a half-life of 0.9 h. 3. After oral and i.v. administration of the labelled compound, the urinary and faecal excretion of radioactivity in 72 h were 61-65% and 31-36% of the dose, respectively. Biliary excretion in bile duct-cannulated animals amounted to 49% of the dose in 72 h. 4. Seven metabolites have been isolated from the plasma or urine and characterized by i.r., n.m.r. and mass spectrometry. They were derived through dihydrodiol formation in the indene ring, hydroxylation of the indene ring and N-acetylation, oxidation and oxidative degradation of the morpholine ring. Some metabolites were excreted as their glucuronic acid or glucose conjugates. The major metabolite appeared to the trans-indandiol analogue of indeloxazine. 5. Possible metabolic pathways of degradation of the morpholine ring are discussed.

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…Further, the metabolic fate of the morpholine moiety is relatively straightforward and in most cases leads to nontoxic metabolites; the ring is predominantly metabolized by CYP3A4 by oxidation leading to a morpholine lactone (eg, linezolid) or lactam (eg, gefitinib or memelotinib) that may be followed by a ring‐opening to for example a corresponding amine or hydroxyl carboxylic acid (Figure ). Morpholine ring opening has been reported with a number of compounds, including timolol, indeloxazine, moclobemide, the renin inhibitor A‐74273, and gefitinib …”

Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers

“…Linkage of morpholine via ring-carbon (not via the nitrogen, as, e.g., in copanlisib) might be the structural prerequisite for this increased oxidative stability [19, 20]. Interestingly, even two methyl groups vicinal to the morpholine oxygen as in sonidegib or other drugs cannot completely abolish oxidative morpholine degradation, although metabolic turnover is diminished significantly by this dimethyl-morpholine structure [21, 22].…”