SIMULTANEOUS QUANTITATIVE AND QUALITATIVE DMPK MEASUREMENTS USING A QUADRUPOLE-TIME-OF-FLIGHT MASS SPECTROMETER
Don S. Richards
Bruker UK Limited, Banner Lane Coventry, UK
Recently there has been considerable interest in simultaneously performing both quantitative and qualitative DMPK analyses in support of small molecule drug discovery. This work the use of a Quadrupole-Time-of-Flight mass spectrometer to obtain clearance data, metabolite identification, structure elucidation and metabolite profiles from P450 microsomal incubations at a drug concentration of 1 μM from a single sample set.
P450 microsomal incubations of commercially available drug substances were prepared at 1 μM concentration. The incubations were sampled and quenched, at intervals to provide a time course over a period of 60 minutes. The analysis of the samples was carried out by LC-MS using a Bruker Maxis Impact Quadrupole-Time-of-Flight mass spectrometer to obtain data suitable for measuring clearance and plotting metabolic profiles. Data dependent MSMS spectra were collected in order to identify and elucidate the structures of the observed metabolites. The results from Verapamil and Haloperidol incubations are presented in detail to demonstrate the Quan/Qual workflow.
The clearance profiles and values are compared to those obtained using a triple quadrupole mass spectrometer