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Received for publication May 23, 2005.
Revised July 25, 2005.
Accepted for publication July 26, 2005.
Increasing reports of time-dependent inhibition of cytochrome P450 suggest further emphasis on interpreting the consequences, either from a pharmacokinetic or toxicological perspective. Two automated, time dependent inhibition assays with an LC-MS-MS end-point are presented. The initial assay utilises human liver microsomes, a single concentration of inhibitor and a single pre-incubation time of thirty minutes. Phenacetin, diclofenac, S-mephenytoin, bufuralol and midazolam are used as substrates for CYPs 1A2, 2C9, 2C19, 2D6 and 3A4 and the assay differentiates between reversible and irreversible inhibition. The second assay uses individual recombinant human CYPs, six inhibitor concentrations and three time points to accurately define kinact and KI. A good correlation is demonstrated between kinact/KI and partition ratio, indicating that both terms are related in describing the efficiency of enzyme inactivation. Despite the single pre-incubation time point of thirty minutes used in the initial assay, a good relationship has been found to exist between the unbound IC50 estimated from this initial screen and the kinact/KI ratio derived from the more extensive subsequent single CYP assay. The higher throughput human liver microsomal assay can therefore generate IC50 values which can be used to predict the pharmacokinetic impact on co-therapies from the estimated kinact/KI ratio, predicted human dose and pharmacokinetics.
Key words:
adverse drug reactions, CYP inhibition, drug-drug interactions, suicide inhibition
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