Pilot in Vivo Structure–Activity Relationship of Dihydromethysticin in Blocking 4‑(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced <i>O</i>⁶‑Methylguanine and Lung Tumor in A/J Mice

(+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure–activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced short-term <i>O</i>⁶-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications

A stable isotope dilution tandem mass spectrometry method of major kavalactones and its applications

<div><p>Kava is regaining its popularity with detailed characterizations warranted. We developed an ultraperformance liquid chromatography high-resolution tandem mass spectrometry (UPLC-MS/MS) method for major kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin and desmethoxyyangonin) with excellent selectivity and specificity. The method has been validated for different matrices following the Food and Drug Administration guidance of analytical procedures and methods validation. The scope of this method has been demonstrated by quantifying these kavalactones in two kava products, characterizing their tissue distribution and pharmacokinetics in mice, and detecting their presence in human urines and plasmas upon kava intake. As expected, the abundances of these kavalactones differed significantly in kava products. All of them exhibited a large volume of distribution with extensive tissue affinity and adequate mean residence time (MRT) in mice. This method also successfully quantified these kavalactones in human body fluids upon kava consumption at the recommended human dose. This UPLC-MS/MS method therefore can be used to characterize kava products and its pharmacokinetics in animals and in humans.</p></div

The amount of kavain, DHK, methysticin, DHM and desmethoxyyangonin in the urine and plasma samples of two subjects pre- and post-kava administration.

<p>The amount of kavain, DHK, methysticin, DHM and desmethoxyyangonin in the urine and plasma samples of two subjects pre- and post-kava administration.</p

Pharmacokinetics and biodistribution of (A) kavain, (B) dihydrokavain, (C) methysticin, (D) dihydromethysticin, and (E) desmethoxyyangonin in the mouse serum, liver, lung, and brain.

<p>Samples were collected 0.5, 1.5, 4, 8, and 24 h after kava treatment. Mice with no kava treatment was used for 0-h timepoint.</p

Reconstructed ion chromatograms at MS/MS scan stage of [²H₂]-DHM, kavain, DHK, methysticin, DHM, and demethoxyyangonin from a control urine, and the urine samples collected from a subject pre- and post-kava.

<p>[²H₂]-DHM was used as the internal standard. The mass extraction window was of ± 5 ppm.</p