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

Abstract

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.

• Authors: Hannah Yejin Kim, Gareth J Veal, Fanfan Zhou, Alan V Boddy
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 74 Issue 12 Pg. 1575-1584 (Dec 2018) ISSN: 1432-1041 [Electronic] Germany
• PMID: 30167756 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antineoplastic
• Carrier Proteins
• Organic Anion Transporters, Sodium-Independent
• SLC22A11 protein, human
• Symporters
• hydrogen-coupled oligopeptide transporter PepT2
• Dactinomycin

Topics

• Adolescent
• Antibiotics, Antineoplastic (pharmacokinetics, therapeutic use)
• Biological Transport
• Carrier Proteins (metabolism)
• Child
• Child, Preschool
• Dactinomycin (pharmacokinetics, therapeutic use)
• Genotype
• HEK293 Cells
• Humans
• Infant
• Infant, Newborn
• Negative Results
• Neoplasms (drug therapy, metabolism)
• Organic Anion Transporters, Sodium-Independent (genetics, metabolism)
• Pharmacogenetics
• Polymorphism, Single Nucleotide (genetics)
• Predictive Value of Tests
• Symporters (genetics, metabolism)
• Young Adult