Drug discovery is a fast growing field and the number of compounds generated daily by the pharmaceutical industry is enormous. The necessity of developing new experimental strategies and analytical methods to rapidly screen the pharmacokinetics (PK) behavior of these compounds becomes a real challenge. A novel strategy to support in vivo PK screening in cassette dosing experiments, using a fully automated system capable of analyzing between 320 to 960 samples a day by instrument in a n-in-one experiment (n = 64 in this work), has been developed. Using an on-line extraction technique, the average observed recovery was 64% using a simple C 18 procedure. A weighted (1/x) linear equation was used to perform standard calibration (0.5 to 500 ng/mL) and the average R value obtained was 0.994 (R 2 = 0.997) for 63 analytes. The limit of detection, defined as a signal-to-noise ratio of 3 or greater, was found to be 25 pg for 41 of the 63 analytes (65%) and 250 pg for 57 of the 63 analytes (90%). The complete automation procedure using the Prospekt-LC-APCI/MS/MS system has substantially improved throughput in the area of drug discovery and bioanalysis.

No abstract

Metabolite profiling is one of the most challenging fields in applied mass spectrometry. Mass spectrometry was used to characterize the metabolites of propranolol, a β‐adrenergic receptor antagonist containing numerous oxidation sites. Propranolol is extensively metabolized, with most metabolites appearing in urine. Urine samples were collected from young adult male Sprague–Dawley rats. Structural identification of various metabolites was performed by LC/MS/MS, using a PE SCIEX triple quadrupole instrument (PE SCIEX API 3000). Metabolites were itemized using several LC/MS/MS techniques, including Q3 full scan and precursor and constant neutral loss experiments. A looped experiment technique revealed the presence of mono‐ and di‐hydroxylated metabolites as well as regio isomers of hydroxy‐ and dihydroxy‐propranolol glucuronides and propranolol glucuronic acid. Propranolol glucuronide was not observed, while the presence of dealkylated metabolites was suggested but not confirmed. Copyright © 1999 John Wiley & Sons, Ltd.

Monohydroxylated derivatives of hexahydrocannabinols were synthesized by catalytic hydrogenation of hydroxytetrahydrocannabinols over a rhodium/alumina catalyst, reduction of tetrahydrocannabinol epoxides with lithium aluminium hydride, or by reaction of tetrahydrocannabinols with hydrogen peroxide. The electron impact-induced fragmentation of their trimethylsilyl ethers was investigated with the aid of deuterium labelling. Most of the compounds gave characteristically different mass spectra with abundant, diagnostically useful fragment ions. As hexahydrocannabinols containing hydroxy groups in all metabolically sensitive positions were readily prepared by the above methods, these provided reference samples for identification of new hydroxylated metabolites of isomeric tetrahydrocannabinols following hydrogenation. The method was validated by application to metabolites of delta-9(11)-tetrahydrocannabinol.

No abstract