Physiological Interpretation of the Lactate to Pyruvate AUC Ratio for Hyperpolarized [1-¹³C]-Pyruvate Studies

To explore the relationship between potentially rate-limiting steps in lactate production and the lactate area-under-the-curve (AUC) to pyruvate AUC ratio for analysis of hyperpolarized (HP) [1-¹³C]-pyruvate data.

Simplifying assumptions are introduced to a pharmacokinetic (PK) model with three physical compartments and two chemical pools to write the AUC ratio in terms of model parameters. Synthetic time curves are used to test sensitivity of the AUC ratio and model parameters to different physiological conditions and acquisition parameters. The simplified model is used to analyze data from patients with head and neck squamous cell carcinoma and determine the rate-limiting step in lactate production.

The simplified model leads to an expression that explicitly demonstrates the relationship between PK model parameters and the AUC ratio. The AUC ratio depends most strongly on intracellular metabolism when pyruvate signal predominantly arises from intracellular space. Simulations confirm that the parameterized AUC ratio can be used to correct for AUC ratio sensitivity to acquisition parameters such as TE. In patient data, the proposed analysis most commonly identified k_ecP as the predominant rate limiting step in lactate production.

Changes observed in the AUC ratio may be driven by changes in pyruvate extravasation, transport into the cell, and/or intracellular metabolism. The proposed model permits parametric representation of the AUC ratio, identification of rate-limiting steps in lactate production, and correction for differences induced by acquisition parameters.