High throughput quantitative assessment of CYP inactivation using 2 concentration points.
To provide a fast and quantitative assessment of CYP inactivation in the drug discovery stage, a mathematical model was derived to calculate enzyme inactivation parameters, k(inact) and K(I), based on experimental data obtained from 2 concentrations of enzyme inactivator. With CYP3A4 inactivators across a range of inactivation potencies, this novel method provided expected rank-ordering of CYP3A4 inactivation. Furthermore, the k(inact) and K(I) values obtained in the two-concentration format correlate generally well with the parameters obtained in the six-concentration format.
Albaugh
Daniel
D
Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877, USA.
Farrell
Thomas
T
Langan
Michael
M
Lai
W George
WG
D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008962:Models, Theoretical
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human