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.
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.
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