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Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):51-66.

Time-dependent CYP inhibition.

Author information

1
AstraZeneca R&D Charnwood, Department of Physical and Metabolic Science, Loughborough, Leicestershire LE11 5RH, UK. rob.riley@astrazeneca.com

Abstract

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.

PMID:
17269894
DOI:
10.1517/17425255.3.1.51
[Indexed for MEDLINE]

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