Ontogenic Expression Of Selected ADME Genes And Their Roles In The Disposition Of Imatinib And SU-1113

Drug metabolizing enzymes(DMEs)and transporters are two important factors that affect drug disposition,efficacy and toxicity.While DMEs play important roles in the biotransformation and metabolic clearance of many therapeutic agents,drug transporters act as carriers or barriers of drug distribution hence maintaining drug concentration gradients in cells,tissues and/or organs.Increasing evidence have demonstrated that DMEs(CYP,UGT,etc.),efflux transporters(P-gp,BCRP,etc.)and uptake transporters(OCT,OATP,etc.)have direct or indirect effects on drug efficacy and toxicities.For a given drug,it is therefore beneficial to understand its disposition mechanism and the relationship between DMEs or transporters and drug's efficacy and toxicity,and such information would lead to safe and effective use of therapeutic agents.During therapeutic intervention,pediatric patients are often facing risks of drug-induced adverse events due to improper use of drugs or immature disposition capability.Because there is a lack of information on changes during growth and development with respect to physiology,organ functions and enzyme systems,children cannot simply be treated as“small adults”.Therefore,it is important to understand ontogenic expression of key ADME genes and their roles in drug disposition.In the present study,juvenile rat was used as an experimental model to explore Mdr1 expression and its role in brain distribution of imatinib and bone toxicity.The utility of the model was also demonstrated using a novel anti-HIV compound.Ontogenic expression of Mdr1 gene and its association with brain distribution of imatinib and serum osteocalcin levels in juvenile rats Imatinib is an inhibitor of BCR-ABL1 tyrosine kinase.Since its approval in 2001 by US FDA,tremendous success has been achieved in the treatment of pediatric chronic myeloid leukemia(CML)and acute myeloid leukemia(AML).While generally well tolerated at therapeutic doses,a primary concern focuses on the effect of imatinib on longitudinal growth as well as bone metabolism in pediatric patients.Bone metabolism is a multifaceted and complex process and the involvement of central nerve system(CNS)has been previously summarized.In addition to neurotransmitters and neurohormones,signal transduction via the peripheral sympathetic nervous system is a key link between bones and CNS.Cumulative evidence suggests that imatinib has the impairment of bone metabolism in pediatric CML patients,which is related to its off-target effects.Since CNS is involved in bone metabolism and remodeling,one intriguing question is the relationship between the brain distribution of imatinib and its underlying bone effects.In the present study,pharmacokinetics of imatinib was examined in juvenile rats at different postpartum days with a focus on brain distribution.Ontogenic expression of the efflux transporter Mdr1(P-gp)was determined in brain tissues from different groups of juvenile rats.Relationship of imatinib brain distribution and serum osteocalcin was determined.Evaluation of a novel antiviral compound SU-1113 in various preclinical systems Mother-to-child transmission(MTCT)is the main transmission route of childhood AIDS.In 2015,an estimated 3.2 million children currently live with human immunodeficiency virus(HIV)worldwide.Children MTCT regimens commonly use zidovudine alone,nevirapine alone,or zidovudine in combination with lamivudine and/or nevirapine.In addition to the development of drug resistance,pediatric patients are more susceptible than adults to side effects.It is thus important to discover and develop a novel and safer anti-HIV drugs for pediatric use.SU-1113 is a novel HIV capsid inhibitor undergoing preclinical research and development.In the present study,metabolism and transport mechanisms of SU-1113 were explored in various in vitro systems.Pharmacokinetics of SU-1113 was examined in juvenile rats at different postpartum days and adult rats.Combination regimens of SU-1113 with other antiviral drugs were also evaluated.Conclusion This dissertation research has demonstrated roles of ontogenic expression of transporters and enzymes in the disposition of drugs in juvenile rats.Information obtained would provide foundation for safe and effective use of drugs in pediatric patients.In the first part of the study,brain distribution of imatinib and related bone toxicity,changes in pharmacokinetic parameters(increase in systemic clearance and brain P-gp expression;decreases in AUC,t_1/2and MRT,and brain distribution)reflected the maturation of metabolic enzymes,P-gp efflux pump and systemic clearance with age.The correlation of imatinib brain distribution to serum osteocalcin levels suggested a CNS role in imatinib-induced changes in bone metabolism.While the link between central and local effects remains to be defined,the current study provides evidence on the role of ontogenic expression of MDR1 gene in the brain distribution of imatinib,which could have a direct effect on bone metabolism in pediatric patients.In the second part of the study,the primary routes of SU-1113 metabolic clearance included oxidation of terminal hydroxyl to carboxylic acid(M5)and O-glucuronidation(M6).SU-1113 was metabolized primarily by CYP3A4 and UGT2B7 to M5 and M6,respectively.The compound was found to be a potent inhibitor against CYP3 A,indicating that SU-1113 has the potential to be a pharmacokinetic enhancer.In addition,high permeability through Caco-2 cell monolayer was observed for SU-1113.SU-1113 is not a substrate but an inhibitor of P-gp.Pharmacokinetic evaluation in adult rats revealed that SU-1113 has an excellent plasma profiles after oral administration.Changes in pharmacokinetic parameters(increase in systemic clearance,decreases in AUC,t_1/2and MRT)were observed in juvenile rats as postpartum day increased.Pharmacokinetic“boosting”effect of SU-1113 was observed when combined with atazanavir(a CYP3 A substrate).Similarly,systemic exposure of SU-1113 was enhanced in the presence of ritonavir(a CYP3 A inhibitor).Using juvenile rat as an experimental model,the current results suggested that ontogenic expression of drug metabolizing enzymes and transporters led to age-related changes in pharmacokinetic profiles of imatinib and SU-1113.The present study also validated the utility of juvenile rats as a valuable mode for pediatric drug development.For marketed drugs as well as compound in development,age-related difference in DME or transporter mediated disposition should be considered.It is believed that such information will lead to safe and effective use of drugs in pediatric patients.