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The role of solute carrier (SLC) transporters in actinomycin D pharmacokinetics in paediatric cancer patients

Lookup NU author(s): Professor Gareth Veal

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Abstract

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Background: Actinomycin D is used for treatment of paediatric cancers; however, a large inter-patient pharmacokinetic (PK) variability and hepatotoxicity are significant limitations to its use and warrant further investigation. Elimination of actinomycin D may be mediated by transporters, as the drug does not seem to undergo significant metabolism. We investigated the role of solute carrier (SLC) transporters in actinomycin D PK. Methods: Fourteen key SLCs were screened through probe substrate uptake inhibition by actinomycin D in HEK293 cells. Uptake of actinomycin D was further studied in candidate SLCs by measuring intracellular actinomycin D using a validated LCMS assay. Pharmacogenetic analysis was conducted for 60 patients (Clinical trial: NCT00900354), who were genotyped for SNPs for OAT4 and PEPT2. Results: OAT4, OCT2, OCT3 and PEPT2 showed significantly lower probe substrate uptake (mean ± SD 75.0 ± 3.5% (p < 0.0001), 74.8 ± 11.2% (p = 0.001), 81.2 ± 14.0% (p = 0.0083) and 70.7 ± 5.7% (p = 0.0188)) compared to that of control. Intracellular accumulation of actinomycin D was greater compared to vector control in OAT4-transfected cells by 1.5- and 1.4-fold at 10 min (p = 0.01) and 20 min (p = 0.03), and in PEPT2-transfected cells by 1.5- and 1.7-fold at 10 min (p = 0.047) and 20 min (p = 0.043), respectively. Subsequent clinical study did not find a significant association between OAT4 rs11231809 and PEPT2 rs2257212 genotypes, and actinomycin D PK parameters such as clearance (CL) and volume of distribution (Vd). Conclusion: Transport of actinomycin D was mediated by OAT4 and PEPT2 in vitro. There was a lack of clinical significance of OAT4 and PEPT2 genotypes as predictors of actinomycin D disposition in paediatric cancer patients.


Publication metadata

Author(s): Kim HY, Veal GJ, Zhou F, Boddy AV

Publication type: Article

Publication status: Published

Journal: European Journal of Clinical Pharmacology

Year: 2018

Volume: 74

Issue: 12

Pages: 1575-1584

Print publication date: 01/12/2018

Online publication date: 30/08/2018

Acceptance date: 15/08/2018

ISSN (print): 0031-6970

ISSN (electronic): 1432-1041

Publisher: Springer Verlag

URL: https://doi.org/10.1007/s00228-018-2544-z

DOI: 10.1007/s00228-018-2544-z


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