Dataset Information

Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.

ABSTRACT:

Background

Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients.

Methods

After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped.

Results

Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001).

Conclusion

The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.

SUBMITTER: Li Q

PROVIDER: S-EPMC6939174 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.

Li Qian Q Wang Kai K Shi Hai-Yan HY Wu Yue-E YE Zhou Yue Y Kan Min M Zheng Yi Y Hao Guo-Xiang GX Yang Xin-Mei XM Yang Yi-Lei YL Su Le-Qun LQ Wang Xiao-Ling XL Jacqz-Aigrain Evelyne E Zhou Jun J Zhao Wei W

Drug design, development and therapy 20191227

<h4>Background</h4>Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of dev ...[more]

PMID: 31920289

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Project description:AimsThe aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.MethodsWe conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88).ResultsIn a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10-12 and P = 3.2 × 10-15 ). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P = 4.69 × 10-5 ) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16-62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P = 2.6 × 10-4 ) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P = .01).ConclusionThese data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.

Project description:The Developmental Eye Movement (DEM) test is commonly used as a clinical visual-verbal ocular motor assessment tool to screen and diagnose reading problems at the onset. No established norm exists for using the DEM test with Mandarin Chinese-speaking Chinese children. This study aims to establish the normative values of the DEM test for the Mandarin Chinese-speaking population in China; it also aims to compare the values with three other published norms for English-, Spanish-, and Cantonese-speaking Chinese children. A random stratified sampling method was used to recruit children from eight kindergartens and eight primary schools in the main urban and suburban areas of Nanjing. A total of 1,425 Mandarin Chinese-speaking children aged 5 to 12 years took the DEM test in Mandarin Chinese. A digital recorder was used to record the process. All of the subjects completed a symptomatology survey, and their DEM scores were determined by a trained tester. The scores were computed using the formula in the DEM manual, except that the "vertical scores" were adjusted by taking the vertical errors into consideration. The results were compared with the three other published norms. In our subjects, a general decrease with age was observed for the four eye movement indexes: vertical score, adjusted horizontal score, ratio, and total error. For both the vertical and adjusted horizontal scores, the Mandarin Chinese-speaking children completed the tests much more quickly than the norms for English- and Spanish-speaking children. However, the same group completed the test slightly more slowly than the norms for Cantonese-speaking children. The differences in the means were significant (P<0.001) in all age groups. For several ages, the scores obtained in this study were significantly different from the reported scores of Cantonese-speaking Chinese children (P<0.005). Compared with English-speaking children, only the vertical score of the 6-year-old group, the vertical-horizontal time ratio of the 8-year-old group and the errors of 9-year-old group had no significant difference (P>0.05); compared with Spanish-speaking children, the scores were statistically significant (P<0.001) for the total error scores of the age groups, except the 6-, 9-, 10-, and 11-year-old age groups (P>0.05). DEM norms may be affected by differences in language, cultural, and educational systems among various ethnicities. The norms of the DEM test are proposed for use with Mandarin Chinese-speaking children in Nanjing and will be proposed for children throughout China.

Dataset Information

Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.

Background

Methods

Results

Conclusion

Publications

Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.

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