Non-invasive19F-NMRS of 5-fluorouracil in pharmacokinetics and pharmacodynamic studies

Abstract

Knowledge of the exact dose and rate at which an antitumor agent is delivered to its target site is postulated to be crucial to proper patient management. It is now possible to obtain such information using non‐invasive 19F‐NMRS (nuclear magnetic resonance spectroscopy) following the administration of 5‐fluorouracil (5‐FU). We have performed such studies in 103 patients with breast, colorectal and other tumors. Measurable 19F signals were detected in 99 of these patients (92.5%). Estimation of the tumoral t1/2 of 5‐FU in these patients revealed that 51 of them (51.5%) exhibited a tumoral t1/2 greater than 20 min, a value we had characterized as indicating drug trapping in the tumor. Of these patients, 46 who received regimen bolus 5‐FU 600 mg/m2 with leucovorin for their treatment have been evaluated. In these patients, the association between trapping and response remains very high (p < .000001). None of the non‐trappers responded to chemotherapy, whereas 70% of the evaluable trappers responded. Details are presented here on the methodology of NMRS data acquisition and on their pharmacokinetic analysis. The potential mechanisms underlying the trapping effect appear to be predicated primarily on transport processes. Suggestions are presented on how such pharmacokinetic imaging studies may extend both our understanding of the mechanism of action of 5‐FU, and how they could be used to optimize patient treatment. © 1998 John Wiley & Sons, Ltd.

Non-invasive molecular and functional imaging of cytosine deaminase and uracil phosphoribosyltransferase fused with red fluorescence protein

“…19 F MRS has previously been proven useful for monitoring the metabolism and pharmacokinetics of 5-FU and other fluorinated drugs in animal models and cancer patients [16,17]. Conversion of 5-FC to 5-FU in xenograft tumors expressing CD has been reported using this technique [18].…”

Noninvasive quantitation of cytosine deaminase transgene expression in human tumor xenografts with in vivo magnetic resonance spectroscopy

“…Because F␤Al production occurs almost exclusively in hepatocytes (47), we suggest that 5-FU produced in the tumor may enter the systemic circulation. The liver extracts Ϸ85% of the 5-FU present in blood at each passage (9) and converts it to F␤Al, which is returned to the blood. Prior et al (48) observed that systemically administered F␤Al accumulates in subcutaneous tumors.…”

“…The broad chemical shift range of fluorine also results in good separation of fluoropyrimidine drugs and their metabolites (3). 19 F-MRS has been used extensively to study the effects of radiation (4), biochemical modulation (5-7), and regional infusion (8) on 5-FU metabolism (9). The quantitative nature of in vivo 19 F-MRS measurements has been confirmed with HPLC (10,11).…”

Target Engagement for PK/PD Modeling and Translational Imaging Biomarkers

“…For example, a 1H MRS study can be used to study choline, creatine, myo -Inositol, Nacetylaspartate, and lipids; and a 31P MRS scan can be used to study phosphocreatine, inorganic phosphates, phosphodiesters, and adenosine triphosphate (ATP) (Dager et al, 2008 ;Soares and Law, 2009 ;van der Graaf, 2010 ). Further, compounds, probes, or ligands that contain an NMR -visible nuclei (e.g., fl uorine -19) can be designed and used to monitor tissue distribution (Wolf et al, 1998 ). The complex chemical exchange of magnetization that occurs can also be leveraged to enable chemical exchange -sensitive techniques, such as chemical exchange saturation transfer ( CEST ) and paramagnetic CEST ( PARACEST ) (Zhang et al, 2003 ;Woods et al, 2006 ;Sherry and Woods, 2008 ).…”