Development of an intravenous microdialysis method for pharmacokinetic investigations in humans.
BACKGROUND
Limited blood volume is a major problem in pharmacokinetic investigations in specific populations, e.g. children. Intravenous microdialysis might help to obtain improved data sets as it is already successfully done in small animals. Since quantification of drugs is crucial in microdialysis, we developed an in vitro method to produce a workable intravenous microdialysis for human use.


METHODS
A specifically designed microdialysis cell consisting of glass was heated to 37 degrees C. The cell was filled with Ringer's solution, plasma or whole blood. A microdialysis probe was inserted into the cell and perfused with Ringer's solution with addition of 4% dextran. The beta-receptor blocker sotalol served as a test drug. The stepwise in vitro evaluation process addressed issues of loss of dialysate, calibration by retrodialysis and relative recovery. These conditions were then applied in an in vivo pilot study to one single healthy volunteer after written informed consent.


RESULTS
To address loss of perfusion fluid 4% of dextran was added and high and constant amounts of dialysate were achieved. To account for changes in the relative recovery a continuous use of retrodialysis by the calibrator atenolol was introduced. The recovery of atenolol was comparable to sotalol. The pharmacokinetic analysis revealed that sotalol concentrations from microdialysates were not different from conventional plasma samples (100+/-11%, n=33) resulting in subsequent comparable pharmacokinetic parameters.


CONCLUSIONS
This stepwise approach using an in vitro device enabled us to demonstrate the determination of pharmacokinetic parameters of sotalol. The most important evaluation step is represented by the continuous use of retrodialysis by the calibrator atenolol because it can account for changes in the relative recovery of the drug. This approach should be a starting point to simplify pharmacokinetic studies in special populations, e.g. in small children, to improve drug treatment.
Elshoff
Jan-Peer
JP
Institut für Experimentelle und Klinische Pharmakologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Läer
Stephanie
S
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001262:Atenolol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003911:Dextrans / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics; D015314:Dialysis Solutions / Q000032:analysis*; D006801:Humans; D007275:Injections, Intravenous; D017551:Microdialysis / Q000295:instrumentation / Q000379:methods*; D010865:Pilot Projects; D013015:Sotalol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D003911:Dextrans; D015314:Dialysis Solutions; D001262:Atenolol; D013015:Sotalol