Plasma pharmacokinetics and CYP3A12-dependent metabolism of c-kit inhibitor imatinib in dogs.
Imatinib is a highly selective tyrosine kinase inhibitor, and is used for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISTs) in humans. The aim of this study is to determine the in vitro and in vivo pharmacokinetics of imatinib in dogs and which cytochrome P450 (CYPs) contribute to its metabolism. Imatinib was administered orally or intravenously to dogs and the time of the peak concentration (T(max)) of imatinib was 4-9 h. The mean half-life was 622 +/- 368 min, and the AUC was 1256 +/- 809 microM * min after oral administration. The range of C0 of intravenously injected dogs was 12-24 microM. The half-life and AUC after intravenous injection were 206 +/- 112 min and 1026 +/- 371 microM * min, respectively. Recombinant system of dog CYP3A12 and CYP2C21 showed that CYP3A12 contributed to the metabolism of imatinib. The inhibition of CYP3A-dependent activity using a rat anti-CYP3A antibody or ketoconazole revealed that CYP3A12 plays a major role in the metabolism of imatinib in dog liver microsomes.
Ishizuka
M
M
Laboratory of Toxicology, Department of Environmental Veterinary Sciences and Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Nagai
S
S
Sakamoto
K Q
KQ
Fujita
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D001549:Benzamides; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D000882:Haplorhini; D006801:Humans; D000068877:Imatinib Mesylate; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; C475779:cytochrome P-450 CYP3A12 (canine); D019009:Proto-Oncogene Proteins c-kit; D007654:Ketoconazole