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

European Journal of Clinical Pharmacology
Hannah Yejin KimAlan V Boddy

Abstract

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. 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. 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...Continue Reading

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Methods Mentioned

BETA
transfection
genotyping

Clinical Trials Mentioned

NCT00900354

Software Mentioned

NONMEM

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