Organ-specific Microcirculatory Mass Transport of Oxycodone in Humans

Abstract

To begin to address the problem of heterogeneity of distribution of oxycodone (OC) in humans, we developed an organ-specific microcirculatory capillary-tissue exchange 2-compartment model for studying regional OC mass transport. The model was developed in silico. It quantifies OC's organ-specific mass transport rates, clearances and recycling, and it considers the effects of blood flow on OC's convective and diffusive transport. What is new is the finding that OC undergoes local recycling at the level of organ-specific capillary-tissue exchange units in humans. Results indicate recycled OC occurs in sufficient amounts to function as a reusable source of circulating OC; which has important implications for OC dosing. Results show the brain, which is central to OC effects only receives about 8% of OC delivered to all organs via the microcirculation. This suggests that differential regulation of receptor binding, trafficking, internalization, or desensitization in the brain likely plays a dominant role in OC's central analgesic effects. Organ-specific OC mass transport kinetics provide new information for OC dosing in pain management. The model promotes patient safety in opioid prescribing because it allows predictions to be made about the relative contribution that OC recycling makes to circulating OC levels. The model indicates that pharmacologic modulation of the microcirculation may give way to site-specific delivery of opioids in the future. Our study demonstrates that translation of bench in silico research data into clinical practice, although still challenging, is feasible and can assist in OC dose regimen design for patient safety.