Validation of a high-throughput absorption, distribution, metabolism, and excretion (ADME) system and results for 60 literature compounds.
A high-throughput analytical system for the support of absorption, distribution, metabolism, and excretion (ADME) was constructed in collaboration with Gubbs Inc. to commercialize corresponding software. We sought to quickly build and validate this system for microsomal clearance assessment using 60 commercially available non-proprietary compounds that are non-DEA-restricted in addition to 36 proprietary Millennium compounds that had already been assessed using a low-throughput infrastructure. The system was constructed such that a approximately 45 second total cycle time was achieved injection-to-injection. Software was successfully coded to enable the analyst to submit multiple batches, and modify multiple methods very quickly for use with Applied Biosystems Analyst 1.3. After acquisition the software was used to simultaneously integrate multiple injection chromatograms, regress the data, and calculate clearance such that all of the data could be easily and immediately reviewed by both bioanalytical and enzymology personnel. Unfortunately, despite an exhaustive search of the literature, we were unable to find a large number of non-proprietary compound data for validation, so we provide such a source of data here. Results are presented for the 60 literature compounds that were assessed. A good correlation was observed between literature results for 16 compounds that we were able to find and the results obtained using the system. The Millennium proprietary compounds that we assessed using both low- and high-throughput approaches also correlated well. We present here a system for the support of high-throughput in vitro ADME analysis and also present the results of 60 non-proprietary, non-DEA-scheduled compounds to facilitate the validation efforts of others. Finally, we present commercially available software to facilitate high-throughput ADME systems in the community.
Yan
Zhixia
Z
Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals Inc., 45 Sidney Street, Cambridge, MA 02474, USA.
Lu
Chuang
C
Wu
Jing-Tao
JT
Elvebak
Larry
L
Brockman
Adam
A
D000042:Absorption; D000327:Adsorption; D000818:Animals; D001331:Automation; D001682:Biological Availability; D006801:Humans; D008861:Microsomes / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results; D012984:Software; D013329:Structure-Activity Relationship
D004364:Pharmaceutical Preparations