Effects Of Developmental Pharmacogenetics On The Pharmacokinetics Of Montelukast And Loratadine

Developmental pharmacogenetics mainly studies the effects of individual development and genetic factors such as drug metabolic enzymes,transporters and receptors on drug disposal,abnormal drug metabolism or adverse drug reactions in children,and finds development factors,protein and gene factors that play a role in the difference of drug reactions,and uses advanced scientific and technological means to select appropriate drugs and doses according to patient's age,weight and metabolism,to predict the results of drug,and to provide more safe,effective and economical individualized treatment for patients,so as to achieve the goal of disease prevention and treatment.Children are significantly influenced by individual factors such as body composition,liver pharmacokinetic activity,transporter activity and kidney development,the pharmacokinetic characteristics are different from those of adults,and are also different from individual.Especially for newborns and infants,if the related genes of a drug are not(fully)expressed at a given age or developmental stage,the correlation between genotype and phenotype may not appear immediately,and the therapeutic effect of drugs will be different.Therefore,understanding the individual occurrence process and the role of gene mutation in drug disposal and adverse drug reactions can provide more valuable information for children's drug treatment decision-making,so as to improve the effectiveness of treatment and reduce adverse drug reactions.Montelukast and loratadine are commonly used therapeutic drugs in pediatrics,and both of them belong to hypermetabolic drugs.Their metabolism in vivo is affected by the corresponding hepatic drug enzymes or transporters,as well as by growth and development factors.As a result,the pharmacokinetic characteristics of montelukast and loratadine are significantly different from those of adults,and there are also significant individual differences,leading to the risk of treatment failure or toxicity.Therefore,it is urgent to study the effects of individual development and genetic factors on drug disposal in children,a special group,in order to improve the safety and effectiveness of drug treatment.Objective:The purpose of this study was to evaluate the effects of developmental pharmacogenetics on the pharmacokinetics of montelukast and loratadine,and to explore the developmental and genetic factors affecting individual differences in montelukast clearance rate and loratadine metabolic rate,so as to provide effective information to meet the needs of individual treatment in children.Methods:After administration of montelukast or loratadine,blood samples were collected from children.For patients taking montelukast,the plasma concentrations were determined by HPLC-FLD.The genetic polymorphisms of CYP2C8*1B(rs7909236)and SLC02B1 c.935G>A(rs12422149)were genotyped.The pharmacokinetic model of pediatric population was established using NONMEM software to estimate the clearance in children.Finally,SPSS statistical analysis software was used to investigate the effects of age,weight and genotype on montelukast clearance.For patients taking loratadine,the plasma concentrations of loratadine and its active metabolite desloratadine,were determined by LC/MS/MS.The genetic polymorphisms of CYP2D6*4(rs3892097),CYP2D6*5(whole gene deletion),CYP2D6*10(rs1065852)and CYP2D6*41(rs28371725)were genotyped.The metabolic rate was determined by calculating the concentration molar ratio of desloratadine to loratadine.Finally,SPSS statistical analysis software was used to investigate the effects of age,weight and genotype on loratadine metabolic rate.Results:Among 50 children taking montelukast,the clearance of montelukast was significantly affected by SLC02B1 c.935G>A(rs12422149)genotype:the clearance of montelukast was significantly higher in subjects with the SLC02B1 c.935GA and C.935AA genotypes compared with that of subjects with the SLC02B1 C.935GG genotype(CL:0.94± 0.26 versus 0.77± 0.77,Mann-Whitney U-test,P = 0.020),and there was also a significant correlation between body weight and montelukast clearance(p<0.0001).The final multiple linear regression analysis showed that the independent factors associated with montelukast clearance were body weight(p = 0.035)and SLC02B1 c.935G>A(p = 0.045).These two factors could explain about 44.1%of the variability in montelukast clearance(R2 = 0.464).Among 40 children taking loratadine,CYP2D6*10 genotype had a significant effect on loratadine metabolic rate:in CYP2D6*10 GA and AA carriers,loratadine metabolic rate was significantly lower than that in wild homozygote GG carriers(metabolic rates were 9.37 ± 7.54 versus 16.94± 14.12,Mann-Whitney U-test,P = 0.028),and there was also a significant correlation between body weight and loratadine metabolic rate(p=0.030).The final multiple linear regression analysis showed that the independent factors associated with loratadine metabolic rate were body weight(p = 0.046)and CYP2D6*10(p = 0.043).These two factors could explain about 16.5%of the variability in loratadine metabolic rate(R2 = 0.207)Conclusions:This study evaluated the effects of developmental and pharmacogenetics factors on montelukast clearance and loratadine metabolic rate in Chinese children.Our results showed that body weight and SLCOB1 c.935G>A(rs12422149)gene polymorphism are important factors affecting the pharmacokinetics of montelukast.Weight and CYP2D6*10 are important factors affecting the pharmacokinetics of loratadine,which provide guidance information for the drug treatment of montelukast and loratadine in Chinese children.