Pharmacokinetics and response to pravastatin in paediatric patients with familial hypercholesterolaemia and in paediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes
| Autor: | Michel Eichelbaum, Kari T. Kivistö, Mia Hedman, Mikko Niemi, Mikko Neuvonen, Pertti J. Neuvonen, Marjatta Antikainen, Christer Holmberg |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_specialty ATP Binding Cassette Transporter Subfamily B Adolescent Genotype medicine.medical_treatment Organic Anion Transporters Single-nucleotide polymorphism 030204 cardiovascular system & hematology 030226 pharmacology & pharmacy Hyperlipoproteinemia Type II 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Polymorphism (computer science) Internal medicine medicine Humans Pharmacology (medical) ATP Binding Cassette Transporter Subfamily B Member 1 Child Pravastatin Pharmacology Heart transplantation Polymorphism Genetic biology Liver-Specific Organic Anion Transporter 1 nutritional and metabolic diseases Original Articles Ciclosporin 3. Good health Transplantation Endocrinology Treatment Outcome Child Preschool biology.protein Heart Transplantation lipids (amino acids peptides and proteins) Female SLCO1B1 medicine.drug |
| Popis: | Our aim was to investigate associations between the single nucleotide polymorphisms (SNPs) in the SLCO1B1 (encoding OATP1B1) and ABCB1 (encoding P-glycoprotein) genes with the pharmacokinetics and efficacy of pravastatin in children with heterozygous familial hypercholesterolaemia (HeFH) and in paediatric cardiac transplant recipients.Twenty children with HeFH (aged 4.9-15.6 years) and 12 cardiac transplant recipients (aged 4.4-18.7 years and receiving triple immunosuppressive medication) who had participated in previous pharmacokinetic and pharmacodynamic studies with pravastatin were genotyped for the -11187GA and 521TC SNPs in the SLCO1B1 gene and for the 2677GT/A and 3435CT SNPs in the ABCB1 gene.Two HeFH patients with the -11187GA genotype had a 81% lower peak plasma pravastatin concentration (Cmax) (difference in means -13.9 ng ml(-1), 95% CI -21.1, -6.7; P0.001) and a 74% smaller area under the plasma concentration-time curve (AUC0, infinity) (-25.3 ng ml(-1) h, 95% CI -35.6, -15.0; P0.0001) and significantly greater increase in high density lipoprotein (HDL) cholesterol after 2 months treatment with pravastatin than patients with the reference genotype. No significant differences were seen in the pharmacokinetics or effects of pravastatin between HeFH patients with the SLCO1B1 521TC and 521TT genotypes. The cardiac transplant recipients with the SLCO1B1 521TC genotype (n = 3) had a 46% lower Cmax (-67.7 ng ml(-1), 95% CI -135.7, 0.3; P = 0.055) and 62% lower AUC(0,24 h) (-228.5 ng ml(-1) h, 95% CI -402.7, -54.3; P = 0.016) and a shorter half-life (t1/2) (0.9 +/- 0.1 vs. 1.3 +/- 0.4 h, P = 0.015) of pravastatin than those with the reference genotype. Decreases in total and low-density lipoprotein cholesterol by pravastatin were significantly smaller, and the increase in HDL-cholesterol was greater in the transplant recipients with the 521TC genotype compared with patients with the 521TT reference genotype.In children with HeFH and in paediatric cardiac transplant recipients receiving immunosuppressive medication, the -11187GA and SLCO1B1 521TC SNPs were associated with decreased plasma concentrations of pravastatin. These differences are opposite to those seen previously in healthy adults. The mechanisms underlying these phenomena are unclear and warrant further study. |
| Databáze: | OpenAIRE |
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