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Pharmacodynamics and pharmacokinetics of hyperpolarized [1‐ 13 C]‐pyruvate in a translational oncologic model
Author(s) -
Perkons Nicholas R.,
Johnson Omar,
Pilla Gabrielle,
Gade Terence P. F.
Publication year - 2021
Publication title -
nmr in biomedicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.278
H-Index - 114
eISSN - 1099-1492
pISSN - 0952-3480
DOI - 10.1002/nbm.4502
Subject(s) - pharmacokinetics , chemistry , metabolite , in vivo , pharmacodynamics , pharmacology , metabolism , lactate dehydrogenase , endocrinology , medicine , biochemistry , biology , enzyme , microbiology and biotechnology
This study investigates the in vivo pharmacokinetics and pharmacodynamics of hyperpolarized [1‐ 13 C]‐pyruvate in a translational cancer model in order to inform the application of dynamic nuclear polarization (DNP)‐enhanced magnetic resonance spectroscopic imaging (MRSI) as a tool for imaging liver cancer. Intratumoral metabolism within autochthonous hepatocellular carcinomas in male Wistar rats was analyzed by MRSI following hyperpolarized [1‐ 13 C]‐pyruvate injections with 80 mM (low dose [LD]) or 160 mM (high dose [HD]) pyruvate. Rats received (i) LD followed by HD injection, (ii) sequential LD injections with or without an interposed lactate dehydrogenase inhibitor (LDHi) injection, or (iii) a single LD injection. A subset of rats in (ii) were sacrificed immediately after imaging, permitting measurement of active LDH concentrations in tumor extracts. Urine and serum were collected before and after injections for rats in (iii). Comparison of LD and HD injections confirmed concentration‐dependent variation of intratumoral metabolite fractions and intermetabolite ratios. In addition, quantification of the lactate‐to‐pyruvate ratio was sensitive to pharmacologic inhibition with intermetabolite ratios correlating with active LDH concentrations in tumor extracts. Finally, comparison of pre‐ and post‐DNP urine collections revealed that pyruvate and the radical source are renally excreted after injection. These data demonstrate that DNP‐MRSI facilitates real‐time quantification of intratumoral metabolism that is repeatable and reflective of intracellular processes. A translational model system confirmed that interpretation requires consideration of probe dose, administration frequency and excretion.