Impact of Genetic Variation on Pravastatin Systemic Exposure in Pediatric Hypercholesterolemia.

Document Type

Article

Publication Date

6-1-2019

Identifier

DOI: 10.1002/cpt.1330

Abstract

This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8-20 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 15; 521CC, n = 2) and wild-type controls (521TT, n = 15) completed a single oral dose pharmacokinetic study. Interindividual variability of pravastatin acid (PVA) exposure within SLCO1B1 genotype groups exceeded the approximately twofold difference in mean PVA exposure observed between SLCO1B1 genotype groups (P > 0.05, q > 0.10). The 3'α-iso-pravastatin acid and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable to previous studies in adults. However, other demographic and physicochemical factors seem to also contribute to interindividual variability in the dose-exposure relationship.

Journal Title

Clinical pharmacology and therapeutics

Volume

105

Issue

6

First Page

1501

Last Page

1512

MeSH Keywords

SLCO1B1 protein, human [Supplementary Concept]; Pravastatin/pharmacokinetics; Hypercholesterolemia; Child; Adolescent; Adult; Dose-Response Relationship, Drug

Keywords

SLCO1B1 genotype

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