Journal
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
Volume 3, Issue 1, Pages 51-66Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/17425255.3.1.51
Keywords
CYP inhibition; mechanism-based; reactive metabolites; time dependent
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Time-dependent inhibition (TDI) of CYP refers to a change in potency during an in vitro incubation or dosing period in vivo. Potential mechanisms include the formation of inhibitory metabolites and mechanism-based inhibition (MBI). In vitro experiments are configured to assess TDI and MBI is inferred, at least initially. MBI is more profound after multiple-dosing and the recovery period is independent of continued drug exposure. Advances in in vitro-in vivo extrapolations for competitive inhibition and the potential relationship between MBI and reactive metabolite-mediated toxicity, have redirected emphasis to CYP TDI. In contrast, with reversible inhibition, strategies for projecting the risks from TDI are less developed and the traditional I/K-i model often yields a dramatic underprediction. This review explores the contribution of TDI to drug-drug interactions and idiosyncratic drug toxicity.
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