PT  - JOURNAL ARTICLE
AU  - Phillip Yates
AU  - Heather Eng
AU  - Li Di
AU  - R. Scott Obach
TI  - Statistical Methods for Analysis of Time-Dependent Inhibition of Cytochrome P450 Enzymes
AID  - 10.1124/dmd.112.047233
DP  - 2012 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 2289--2296
VI  - 40
IP  - 12
4099  - http://dmd.aspetjournals.org/content/40/12/2289.short
4100  - http://dmd.aspetjournals.org/content/40/12/2289.full
SO  - Drug Metab Dispos2012 Dec 01; 40
AB  - Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes, especially CYP3A4, is an important attribute of drugs in evaluating the potential for pharmacokinetic drug-drug interactions. The analysis of TDI data for P450 enzymes can be challenging, yet it is important to be able to reliably evaluate whether a drug is a TDI or not, and if so, how best to derive the inactivation kinetic parameters KI and kinact. In the present investigation a two-step statistical evaluation was developed to evaluate CYP3A4 TDI data. In the first step, a two-sided two-sample z-test is used to compare the kobs values measured in the absence and presence of the test compound to answer the question of whether the test compound is a TDI or not. In the second step, kobs values are plotted versus both [I] and ln[I] to determine whether a significant correlation exists, which can then inform the investigator of whether the inactivation kinetic parameters, KI and kinact, can be reliably estimated. Use of this two-step statistical evaluation is illustrated with the examination of five drugs of varying capabilities to inactivate CYP3A4: ketoconazole, erythromycin, raloxifene, rosiglitazone, and pioglitazone. The use of a set statistical algorithm offers a more robust and objective approach to the analysis of P450 TDI data than frequently employed empirically derived or heuristic approaches.