AIMS: To determine blood binding parameters of imatinib and its metabolite CGP74588 in humans and non-human species. METHODS: The blood distribution and protein binding of imatinib and CGP74588 were determined in vitro using (14)C labelled compounds. RESULTS: The mean fraction of imatinib in plasma (f(p)) was 45% in dog, 50% in mouse, 65% in rat, 70% in healthy humans and up to 92% in acute lymphatic leukaemia (AML) patients. Similarly, f(p) for CGP74588 was low in dog and monkey (30%), higher in rat, mouse and humans (70%) and highest in some AML patients (90%). The unbound fraction of imatinib and CGP74588 in plasma was lower in rat, mouse, healthy humans and AML patients (2.3-6.5% at concentrations < or = 5000 ng ml(-1)) compared to monkey and dog (7.6-19%). Both compounds displayed high binding to human alpha(1)-acid glycoprotein. AML patients had a reduced haematocrit and showed greatest variability in their blood binding parameters. CONCLUSION: Imatinib and CGP74588 displayed very similar blood binding parameters within all species/groups investigated. The five species clustered into two distinct groups with rat, mouse and humans being clearly different from dog and monkey. For both compounds, higher protein binding was associated with a decreased partitioning into blood cells.
AIMS: To determine blood binding parameters of imatinib and its metabolite CGP74588 in humans and non-human species. METHODS: The blood distribution and protein binding of imatinib and CGP74588 were determined in vitro using (14)C labelled compounds. RESULTS: The mean fraction of imatinib in plasma (f(p)) was 45% in dog, 50% in mouse, 65% in rat, 70% in healthy humans and up to 92% in acute lymphatic leukaemia (AML) patients. Similarly, f(p) for CGP74588 was low in dog and monkey (30%), higher in rat, mouse and humans (70%) and highest in some AMLpatients (90%). The unbound fraction of imatinib and CGP74588 in plasma was lower in rat, mouse, healthy humans and AMLpatients (2.3-6.5% at concentrations < or = 5000 ng ml(-1)) compared to monkey and dog (7.6-19%). Both compounds displayed high binding to human alpha(1)-acid glycoprotein. AMLpatients had a reduced haematocrit and showed greatest variability in their blood binding parameters. CONCLUSION:Imatinib and CGP74588 displayed very similar blood binding parameters within all species/groups investigated. The five species clustered into two distinct groups with rat, mouse and humans being clearly different from dog and monkey. For both compounds, higher protein binding was associated with a decreased partitioning into blood cells.
Authors: Martin H Cohen; Grant Williams; John R Johnson; John Duan; Jogarao Gobburu; Atiqur Rahman; Kimberly Benson; John Leighton; Sung K Kim; Rebecca Wood; Mark Rothmann; Gang Chen; Khin Maung U; Ann M Staten; Richard Pazdur Journal: Clin Cancer Res Date: 2002-05 Impact factor: 12.531
Authors: Heather G Jørgensen; Moira A Elliott; Elaine K Allan; Christine E Carr; Tessa L Holyoake; Kevin D Smith Journal: Blood Date: 2002-01-15 Impact factor: 22.113
Authors: Bin Peng; Michael Hayes; Debra Resta; Amy Racine-Poon; Brian J Druker; Moshe Talpaz; Charles L Sawyers; Marianne Rosamilia; John Ford; Peter Lloyd; Renaud Capdeville Journal: J Clin Oncol Date: 2004-03-01 Impact factor: 44.544
Authors: George D Demetri; Margaret von Mehren; Charles D Blanke; Annick D Van den Abbeele; Burton Eisenberg; Peter J Roberts; Michael C Heinrich; David A Tuveson; Samuel Singer; Milos Janicek; Jonathan A Fletcher; Stuart G Silverman; Sandra L Silberman; Renaud Capdeville; Beate Kiese; Bin Peng; Sasa Dimitrijevic; Brian J Druker; Christopher Corless; Christopher D M Fletcher; Heikki Joensuu Journal: N Engl J Med Date: 2002-08-15 Impact factor: 91.245
Authors: N Widmer; L A Decosterd; C Csajka; S Leyvraz; M A Duchosal; A Rosselet; B Rochat; C B Eap; H Henry; J Biollaz; T Buclin Journal: Br J Clin Pharmacol Date: 2006-07 Impact factor: 4.335
Authors: H Schmidli; B Peng; G-J Riviere; R Capdeville; M Hensley; I Gathmann; A E Bolton; A Racine-Poon Journal: Br J Clin Pharmacol Date: 2005-07 Impact factor: 4.335
Authors: Prashant B Nigade; Jayasagar Gundu; K Sreedhara Pai; Kumar V S Nemmani Journal: Eur J Drug Metab Pharmacokinet Date: 2017-10 Impact factor: 2.441