title: The kinetic deuterium isotope effect as applied to metabolic deactivation of imatinib to the des-methyl metabolite, CGP74588.
abstract: There has recently been a burgeoning interest in impeding drug metabolism by replacing hydrogen atoms with deuterium to invoke a kinetic isotope effect. Imatinib, a front-line therapy for both chronic myeloid leukemia and of gastrointestinal stromal tumours, is often substantially metabolised via N-demethylation to the significantly less active CGP74588. Since deuterium-carbon bonds are stronger than hydrogen-carbon bonds, we hypothesised that the N-trideuteromethyl analogue of imatinib might be subject to a reduced metabolic turnover as compared to imatinib and lead to different pharmacokinetic properties, and hence improved efficacy, in vivo. Consequently, we investigated whether the N-trideuteromethyl analogue would maintain target inhibition and show a reduced propensity for N-demethylation in in vitro assays with liver microsomes and following oral administration to rats. The N-trideuteromethyl compound exhibited similar activity as a tyrosine kinase inhibitor as imatinib and similar efficacy as an antiproliferative in cellular assays. In comparison to imatinib, the trideuterated analogue also showed reduced N-demethylation upon incubation with both rat and human liver microsomes, consistent with a deuterium isotope effect. However, the reduced in vitro metabolism did not translate into increased exposure of the N-trideuteromethyl analogue following intravenous administration of the compound to rats and no significant difference was observed for the formation of the N-desmethyl metabolite from either parent drug.
authors.affiliation: Disease Area Oncology, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland. paul.manley@pharma.novartis.com
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Reiner
authors.initials: R
authors.lastname: Aichholz
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001549:Benzamides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001711:Biotransformation; D003903:Deuterium; D006801:Humans; D006859:Hydrogen; D000068877:Imatinib Mesylate; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C464561:CGP 74588; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D006859:Hydrogen; D000068877:Imatinib Mesylate; D003903:Deuterium