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Can Ki values for direct inhibition of CYP enzymes be reliably estimated from IC50 values?

  • Published on September 14, 2011
  • Enzyme Inhibition
  • Scientific Posters

Regulatory agencies recommend that the potential for a drug candidate to cause clinically relevant, direct inhibition of cytochrome P450 (CYP) enzymes be estimated based on the ratio of [I]/Ki (or 1+[I]/Ki) where [I] is the in vivo concentration of drug candidate and Ki is the dissociation constant for the enzyme-inhibitor complex for direct inhibition (US FDA, 2006).

Typically, inhibition of CYP enzymes by a drug candidate is first evaluated in vitro by determining the concentration of drug candidate that causes 50% inhibition of a specific CYP enzyme activity (IC50) using a marker substrate concentration approximately equal to Km for the marker substrate reaction. Determining the mechanism of direct inhibition (competitive, uncompetitive, noncompetitive and mixed) and measuring the Ki value requires an in vitro evaluation of the effects of multiple concentrations of the drug candidate versus multiple concentrations of CYP probe substrate (the former spanning Ki and later spanning Km).

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