Simultaneous, Seconds-Resolved Doxorubicin Measurements in the Blood and Subcutaneous Interstitial Fluid Identify Quantitative Pharmacokinetic Relationships between the Two

Abstract

The kinetics with which chemotherapeutics distribute into solid tissues, including their sites of both action and toxicity, remains poorly characterized. This is due to the limited temporal resolution of traditional methods of measuring drug concentrations in the body, all of which employ sample collection (e.g., via a blood draw or microdialysis) followed by benchtop analysis. Here, we have used electrochemical aptamer-based (EAB) sensors to perform simultaneous, 12 s resolution, nanomolar-precision measurements of the chemotherapeutic doxorubicin in the jugular vein (plasma) and subcutaneous space (interstitial fluid) of live rats. The resulting data sets identify predictively strong correlations between its plasma and solid-tissue pharmacokinetics in terms of both cumulative (area under the curve) and maximum exposure. In contrast, the correlations between delivered body-mass-adjusted and body-surface-area-adjusted doses and drug exposure in both the plasma and solid tissue are relatively poor. The latter observation highlights the need for therapeutic drug monitoring, and the former observation shows the potential value of employing subcutaneous EAB sensors as a convenient, minimally invasive, high-precision means of performing such monitoring. The high time density of our two-compartment data sets also provides unprecedented opportunities to model the distribution of a drug from the central compartment to a distal physiological compartment. We find that the preferred description of doxorubicin transport into the solid tissues for five of our six data sets is a three-compartment model composed of the vein (plasma), the interstitial fluid, and an unobserved third compartment distal to the interstitial fluid, with this additional compartment presumably representing intracellular fluid.