The concentration near an enzyme may differ from a convenient plasma or nominal laboratory concentration.
The researchers examined ten time-dependent CYP3A inhibitors using midazolam hydroxylation in liver microsomes. They estimated unbound cytosolic inhibitor concentrations in hepatocytes and incorporated them into static interaction predictions. Correcting for cellular availability generally improved agreement with clinical interaction data.
The approach still depended on model assumptions and did not directly measure inhibitor availability in intestinal cells. Hepatocyte-derived parameters may not transfer unchanged to enterocytes. Improved prediction across selected drugs is not exact prediction for every medicine or patient.
For pharmacokinetic testimony, identify which concentration is measured and which is estimated. Total plasma concentration, unbound concentration and intracellular availability answer different questions. This study supports more careful interaction modeling, not a claim that a laboratory inhibition number alone establishes the magnitude of a benzodiazepine interaction.
Source reviewed: Improved predictions of time dependent drug drug interactions by determination of cytosolic drug con (PMC6458156). Forensic applications above are interpretive analysis of the supplied publication.
Related reading: Matched Liver Donors Still Produced Different Midazolam Clearance Estimates in Two Lab Systems.