Population Pharmacokinetics Of Cyclosporine In Paediatric Patients And The Affect Of Ontogeny On The Expression Of CYP3A And Nuclear Receptors In Rats

ObjectivesThe aim of this study was to develop a population pharmacokinetic model of cyclosporin(CsA) in pediatric aplastic anemia patients,thereby optimizing its therapeutic effects in clinical trials.MethodsWe have prospectively collected 1611 routine samples of average steady-state CsA trough concentration in 222 pediatric patients with hematologic disease in a Chinese population.These data were analyzed using the nonlinear mixed-model program(NONMEM).Based on the influence of numerous tested covariates(i.e.,age, height,weight,BSA,GFR),a population pharmacokinetic model of CsA was developed and further validated by data splitting.ResultsAfter oral administration,the whole blood steady-state trough concentration of CsA could be well described by a Michaelis-Menten model,in which four covariates (i.e.,age,BSA,GFR,and stanozolol) were included.Furthermore,the Michaelis-Menten constants,Vm and Km with interindividual variation in parenthesis, were estimated to be 206 mg/d(28%) and 39.9μg/L(67.7%),respectively.The intraindividual variation of V_m and K_m was 29.2%.The final model was described as: DR=([206+9.64×(AGE-8.26)+22.5×(BSA-1.06)]×Exp(η₁)×Css)/({[39.9+3.6l×(GFR-1565]×(1+0.868×STZ)}×Exp(η₂)+Css)+εConclusionsIn conclusion,pharrnacokinetic parameters of CsA in pediatric aplastic anemia patients may be largely influenced by age,BSA,GFR and Stanzolol.We propose that our CsA population pharrnaeokinetie model,combined with the Bayesian forecasting method,may optimize the dosage of CsA in clinical trials. ObjectivesThe aim of this study was to investigate the effects of birth weight on the expression and regulation of CYP3A1/2 as well as its nuclear receptors,including PXR, CAR,and HNF4a in newborn rats.MethodsPregnant rats were randomly divided into two groups:nourished and under-nourished.The offspring of nourished rats with birth weight between 5.2～7.2g were defined as normal-birth-weight group(NBW,n=15),while those of undernourished rats with birth weight under 5.2g were defined as low-birth-weight group(LBW,n=15).Additionally,the offspring of nourished rats with birth weight above 7.2g were defined as high-birth-weight group(HBW,n=15).Hepatic mRNA expression of CYP3A1,PXR.,CAR and HNF4αwas detected by quantitative real-time RT-PCR.Immunohistochemistry was performed to investigate the corresponding protein expression and localization.Protein expression was evaluated by using a score corresponding to the sum of both staining intensity and percentage of positive hepatocytes.ResultsLow birth weight could significantly affect mRNA expression of CYP3A2 and CAR,and protein expression of CYP3A1 and CAR.In contrast,the high birth weight could significant affect the mRNA levels of CYP3A2 and HNF4α,and also the protein levels of CYP3A1 and HNF4a expression.CYP3A1 mRNA expression correlated with that of CYP3A2 and HNF4a.ConclusionsIn conclusion,birth weight could influence the production of several drug metabolism enzymes(i.e.,CYP3A1/2,and its nuclear receptors) in newborn rats, which should be taken into consideration when delivering medication to LBW and HBW infants in humans. ObjectivesIn this study,we have aimed to investigate the effects of low birth weight and high-lipid diet on the expression and regulation of CYP3A1/2 as well as its nuclear receptors,including PXR,CAR,and HNF4α,in female rats during development.MethodsThe LBW animal model was established as mentioned above in Part One.Gene expression analysis(mRNA and protein levels) was performed as described previously. According to different birth weight and diet feeding,rats were divided into 4 groups as following:1.Normal birth weight-normal diet group,NN-group2.Normal birth weight-high lipid and high energy group,NH-group3.Low birth weight-normal diet group,LN-group4.Low birth weight-high lipid and high energy group,LH-groupLivers were isolated from each group,and subsequently used for gene expression study (i.e.,mRNA and protein levels) at 3,7,14,21,28,56,84 days after birth(n=6-8 per group).ResultsThe hepatic expression of CYP3A1/2 and its nuclear receptors(i.e.,PXR,CAR, and HNF4α) was found to be age'dependent in rats.The effects of low birth weight on the expression of CYP3A1/2,PXR,CAR and HNF4αcan persist after birth.In particular,the expression of PXR and CAR was dramatically altered under the LBW situation,which was correlated with the expression of CYP3A1/2.Furthermore,the expression of CYP3A1/2 and their nuclear receptors,especially the HNF4α,was largely influenced by the high-lipid diet feeding in rats.ConclusionIn conclusion,the hepatic expression and modulation of CYP3A1/2 and its nuclear receptors(i.e.,PXR,CAR,and HNF4α) were influenced by both birth weight and high-lipid diet feeding in developing rats.We propose that the alteration and interaction of CYP3A and its nuclear receptors have potential clinical implications for optimal medication in low birth weigh and fat children.