IEEE Trans Biomed Eng. 2023 Oct;70(10):2905-2913. doi: 10.1109/TBME.2023.3269665. Epub 2023 Sep 27.
Hyperpolarized [1-C]-pyruvate magnetic resonance imaging is an emerging metabolic imaging method that offers unprecedented spatiotemporal resolution for monitoring tumor metabolism in vivo. To establish robust imaging biomarkers of metabolism, we must characterize phenomena that may modulate the apparent pyruvate-to-lactate conversion rate (k). Here, we investigate the potential effect of diffusion on pyruvate-to-lactate conversion, as failure to account for diffusion in pharmacokinetic analysis may obscure true intracellular chemical conversion rates.
Changes in hyperpolarized pyruvate and lactate signal were calculated using a finite-difference time domain simulation of a two-dimensional tissue model. Signal evolution curves with intracellular k values from 0.02 to 1.00 s were analyzed using spatially invariant one-compartment and two-compartment pharmacokinetic models. A second spatially variant simulation incorporating compartmental instantaneous mixing was fit with the same one-compartment model.
When fitting with the one-compartment model, apparent k underestimated intracellular k by approximately 50% at an intracellular k of 0.02 s. This underestimation increased for larger k values. However, fitting the instantaneous mixing curves showed that diffusion accounted for only a small part of this underestimation. Fitting with the two-compartment model yielded more accurate intracellular k values.
This work suggests diffusion is not a significant rate-limiting factor in pyruvate-to-lactate conversion given that our model assumptions hold true. In higher order models, diffusion effects may be accounted for by a term characterizing metabolite transport. Pharmacokinetic models used to analyze hyperpolarized pyruvate signal evolution should focus on carefully selecting the analytical model for fitting rather than accounting for diffusion effects.
超极化 [1-C]-丙酮酸磁共振成像是一种新兴的代谢成像方法，为监测体内肿瘤代谢提供了前所未有的时空分辨率。为了建立可靠的代谢成像生物标志物，我们必须描述可能调节丙酮酸到乳酸转化率（k）的现象。在这里，我们研究了扩散对丙酮酸到乳酸转化的潜在影响，因为在药代动力学分析中如果没有考虑扩散，可能会掩盖真正的细胞内化学转化速率。
使用二维组织模型的有限差分时域模拟计算超极化丙酮酸和乳酸信号的变化。使用空间不变单室和双室药代动力学模型分析具有 0.02 到 1.00 s 之间的细胞内 k 值的信号演化曲线。包含瞬时混合的空间可变模拟与相同的单室模型拟合。
在用单室模型拟合时，在细胞内 k 值为 0.02 s 时，表观 k 值低估了细胞内 k 值约 50%。随着 k 值的增大，这种低估会增加。然而，拟合瞬时混合曲线表明，扩散仅占这种低估的一小部分。用双室模型拟合可以得到更准确的细胞内 k 值。
这项工作表明，扩散不是丙酮酸到乳酸转化的主要限速因素，只要我们的模型假设成立。在更高阶模型中，扩散效应可以通过描述代谢物运输的术语来解释。用于分析超极化丙酮酸信号演化的药代动力学模型应侧重于仔细选择用于拟合的分析模型，而不是考虑扩散效应。
