Vein‐to‐brain: Simultaneous, seconds‐resolved measurements of intracranial and intravenous drug levels provide a highly time‐resolved picture of drug transport

Abstract

Drug action, particularly for centrally-active compounds, is critically dependent upon the transport of molecules across physiological barriers to reach the site of action. The ability to measure specific molecules simultaneously at multiple sites within the body and with seconds time resolution could revolutionize our understanding of drug transport, metabolism, and elimination. It could, for example, improve our understanding of the blood-brain and blood-cerebral spinal fluid barriers that protect the central nervous system by regulating the transfer of molecules to and from these central compartments. As a proof-of-principle demonstration of this, here we describe the use of electrochemical aptamer-based (EAB) sensors to measure transport of the antibiotic vancomycin (a drug that is subject to negligible metabolism or biotransformation) from the plasma to the cerebrospinal fluid of live rats with 7 s temporal resolution. Doing so, we show that, while the collection of hundreds of concentration values over a single drug lifetime enables high-precision estimates of the parameters describing transport, ambiguity is introduced by a mathematical equivalence that produces two divergent pharmacokinetics parameter sets that fit the data equally well. The inclusion of simultaneous, intravenous measurements, however, resolves this equivalence, enabling high-precision (±5 to ±20% at 95% confidence levels) estimates of the pharmacokinetic parameters describing inter-compartmental transport in individual animals. The availability of simultaneous “in-brain” and “in-vein” measurements also provides an opportunity to relax the assumptions almost universally employed in prior compartmental models of drug transport, allowing us to quantitatively address (rather than simply assume), for example, whether the targeted drug is potentially metabolized in brain tissue or actively transported into or out of the ventricles. In sum, the present work highlight the potential of EAB sensors for the tracking intercompartmental molecular transport in the living body, which would not only increase our ability to understand -and therefore modulate- such transport, but could be used as a powerful preclinical tool during drug development to screen drug candidates more effectively in vivo. Such an advance would allow swifter, more accurate, exploration of the clinical impact of novel drug candidates, opening the door for better dosing regimens, as well as streamlining and increasing cost effectiveness of novel drug development.