Ontogenic expression of key ADME genes and their roles in imatinib‐induced toxicity in juvenile rats

Abstract

Imatinib is an oral tyrosine kinase inhibitor that is approved for the treatment of pediatric chronic myeloid leukemia. Prepubertal growth impairment has been reported to be a major neurologic adverse effect of long‐term imatinib treatment in children. Numerous studies have demonstrated that cytochrome P450 3A4 and ABCB1 are major ADME genes that play critical roles in biotransformation and brain disposition of imatnib. In the present study, we first evaluated the relationships between ontogentic expression of ADME genes and exposure of imatinib in a neonatal rat model. The expression of Cyp3a1 and Abcb1 of rats from different postpartum days (PPD) were determined at mRNA and protein levels, and results revealed that their expression increased with age. Pharmacokinetic studies after single oral dose of imatinib (30 mg/kg) given to 7‐, 14‐, 21‐, 28‐ or 35‐day‐old rats demonstrated that brain distribution of imatinib decreased with age, with > 20 fold decrease in PPD35 rats compared with PPD7 rats, consistent with mRNA and protein expression levels of key ADME genes. Juvenile rat toxicity studies with oral imatinib were conducted to examine the relationship between Cyp3a1 and Abcb1 gene expression and growth (in particular bone formation) retardation. Preliminary data suggest a distinctive inhibitory effect of imatinib on bone growth in neonatal rats. Mechanistic investigations using osteoblasts and in vivo neonatal rat model are on‐going to delineate regulatory network between imatinib disposition and bone formation.Support or Funding InformationThe current work was supported in part by a grant from Soochow University, Suzhou, China [Grant No. Q413200711], and a grant from the National Science Foundation of China [Grant No. 81473278].