In Vivo Absorption, Distribution, Excretion, and Metabolism of a New Herbicide, Methiozolin, in Rats following Oral Administration

Abstract

Methiozolin [5-(2,6-difluorobenzyl)oxymethyl-5-methyl-3-(3-methylthiophen-2-yl)-1,2-isoxazoline] is a new turf herbicide that controls annual bluegrass in various cool- and warm-season turfgrasses. The present study is the first report elucidating absorption, tissue distribution, excretion, and metabolism of methiozolin in rats. The pharmacokinetic parameters in the blood were observed as follows: t(max) = 6 h, C(max) = 168.7 μg equiv/mL, t(½) = 49.4 h, AUC₁₂₀ = 9921.5 μg equiv·h/mL, and clearance = 39.2 mL/h/kg. Those parameters and the depletion curve for ¹⁴C in the plasma were very similar to those in the blood. Total excretion through urine and feces was 24.3 and 68.9%, respectively, during 120 h after administration; however, there was no excretion through expired air. The radioactivity excreted through bile was 40.1% of that administered. Excreted radioactivity peaked between 24 and 48 h, showing 51.0% of total excretion within 48 h. The orally administered ¹⁴C distributed across various tissues within 12 h after administration, showing 14.0% of the dosed, and was eliminated from all tissues without accumulation. Numerous minor metabolites (<4% of the dosed) in urine and fecal extract were detected within 72 h, and two of those were identified. The identified metabolites were Met-1 (glucuronic acid conjugate), 6-[5-(5-((2,6-difluorobenzyloxy)methyl)-4,5-dihydro-5-methylisoxazol-3-yl)-4-methylthiophen-2-yloxy]-tetrahydro-3,4,5-trihydroxy-2H-pyran-2-carboxylic acid, and Met-2, [2-(5-((2,6-difluorobenzyloxy)methyl)-4,5-dihydro-5-methylisoxazol-3-yl)thiophen-3-yl]methanol. Conclusively, methiozolin was shown to be readily absorbed in the gastrointestinal tract, distributed throughout the tissues within 12 h, metabolized extensively, and eliminated through urine and feces mostly within 48 h, without tissue accumulation.

Discovery of Novel Pyrazole–Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

“…In our work, the in vitro activity of some compounds was better than that of the control, but they did not show obvious control effects on the tested weeds. As we know, in plants, the process of absorption, conduction, and metabolism is very important for herbicides to exert their effects. , These factors were very likely the cause of the differences in activity observed in vitro and in vivo .…”

Copper-catalyzed radical oxyallylation of olefins for the construction of alkene-containing isoxazolines

“…Encouraged by the works of Han, 29,30 Wang, 31 and our group 32 on the copper-catalyzed iminoxyl radical-mediated oxyfunctionalization of alkenes, we envisioned that iminoxyl radical may also be involved in the oxyallylation with allyl sulfones. Herein, we describe more convenient method, which has led to the construction of useful isoxazolines [33][34][35][36][37][38][39][40][41][42][43] and the installation of versatile alkenyl groups in one transformation. It is expected that the resulting C=C bond will serve as a useful precursor for obtaining other isoxazoline-containing compounds.…”

Visible‐Light‐Induced Radical Di‐ and Trifluoromethylation of β, γ‐Unsaturated Oximes: Synthesis of Di‐ and Trifluoromethylated Isoxazolines

“…As a privileged class of structural scaffold, the isoxazoline core is widely present in numerous natural products, pharmaceuticals and biologically active molecules Moreover, isoxazolines are valuable intermediates to access various synthetic structures, as well as chiral ligands in asymmetric synthesis . Consequently, tremendous efforts have been made to develop novel and elegant strategies for the formation of isoxazolines .…”