A rapid and efficient analytical method for the quantification of a novel anticholinergic compound, R‐phencynonate, by stable isotope‐dilution LC–MS/MS and its application to bioavailability and dose proportionality studies

Abstract

A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.

The stereoselective pharmacokinetics of the desmethyl‐phencynonate hydrochloride in beagle dogs

“…Our institute discovered many new anticholinergic chemical entity such as penehyclidine, 8,9 phencynonate, 10,11 and desmethyl -phencynonate hydrochloride for the treatment of Parkinson's disease. 12,13 The desmethyl-phencynonate hydrochloride is an active metabolite of phencynonate, which exhibits more potent anticholinergic effects and anti-parkinsonism activities than phencynonate. Desmethyl-phencynonate hydrochloride is clinically more effective than phencynonate and artane.…”

“…Therefore, M 4 acetylcholine receptor are very important target of drug treatment and M 4 acetylcholine receptor antagonist is an important direction for new drug research. Our institute discovered many new anticholinergic chemical entity such as penehyclidine, 8,9 phencynonate, 10,11 and desmethyl ‐ phencynonate hydrochloride for the treatment of Parkinson's disease 12,13 …”