Karin Tunblad, Margareta Hammarlund-Udenaes and Niclas Jonsson
Division of Pharmacokinetics and Drug Therapy, Uppsala University, Sweden
Background: Microdialysis measures the unbound concentration of a drug in a specific tissue. The microdialysis probe is perfused with a Ringer solution, and dialysate samples are collected in intervals. Since there is a flow through the probe, the concentration in the dialysate will be a fraction of the true extracellular concentration. This fraction is the recovery.
Objectives: The aim of this study was to compare a new model for data from a microdialysis experiment to a previously used model. This is exemplified with morphine-6-glucuronide (M6G) data.
Methods: A CMA/12 microdialysis probe was placed in striatum, and a CMA/20 probe was implanted into the jugular vein of ten Sprague-Dawley rats. The recovery of the probes was estimated using retrodialysis by drug. M6G was administered as a 4-h exponential i.v. infusion aiming at 3000 ng/ml in blood. The experiment was repeated on Day 2 with the addition of probenecid. Fractions of dialysate were collected in 10-15 min intervals, and arterial blood samples (total concentrations) were drawn at predefined time points.
The modelling was performed in NONMEM using the first order conditional estimation method with interaction. In the previous modelling approach the average venous concentrations in each collection interval were corrected for the average recovery calculated from the retrodialysis period. Thereafter the arterial concentrations, corrected for the individual protein binding by comparing the unbound AUC in venous blood to the total AUC in arterial blood, were modelled. The analysis of the brain concentrations was conditioned on the individual parameters from the arterial analysis.
In the new approach the idea is to (i) model all the data simultaneously, i.e the recovery the venous microdialysis data and the arterial data, and (ii) to model the venous data as they were collected in intervals using an output compartment. This handling of the venous data is comparable with urine data, which also is collected in intervals.
Conclusion: The advantage with the new modelling approach is that all data are described with a single model, that less assumptions has to be made and that it is now possible to simulate all the steps in a microdialysis experiment. The latter allows for rational study design optimisation.
Reference: PAGE 12 () Abstr 435 [www.page-meeting.org/?abstract=435]
Poster: poster