Pharmacokinetic and pharmacodynamic relationships are of central importance in defining the efficacy of anticancer drugs. This is critically determined for many newly licensed and emerging anticancer drugs by their rate of metabolism by the cytochrome P450-dependent monooxygenase system.There is profound individual variability in the activity of these enzymes that can result either in lack of drug efficacy or in enhanced side effects. There are major species differences in these enzymes between small animals and man, both in P450 regulation and multiplicity. In order to develop models that more closely resemble the human situation we have humanised mice for the major cytochrome P450s involved in drug disposition together with the transcription factors that regulate their expression.We have created complex gene knockouts and humanisations where the major gene clusters have been deleted and substituted for their human counterparts.A mouse model has been created where the major enzymes involved in drug disposition in man are expressed in a single animal.These models have been applied to establish pharmacokinetic and pharmacodynamic relationships for tyrosine kinase and B-Raf inhibitors in the treatment of cancer. These data will be described in this presentation.

Thank you for to all who contributed to this work:

C Roland Wolf¹, Nico Scheer², Anje Rode², Stephanie L Sharp¹, Kenneth AZ MacLeod¹, Zoe Riches¹, Michael MJ McMahon¹, Yury Kapelyukh¹, Lesley M McLaughlin¹ and Colin J Henderson¹.

¹University of Dundee Medical Research Institute, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK ²TaconicArtemis, Neurather Ring 1, Cologne 51063, Germany