In vivo drug-response measurements in target tissues by microdialysis.
To study the suitability of the microdialysis technique for the measurement of target tissue pharmacodynamics in humans, the model compounds theophylline, milrinone, and compound 48/80 were administered locally by means of reversed microdialysis to the interstitial space of skeletal muscle or skin in 24 healthy volunteers. Simultaneously, interstitial concentrations of cyclic adenosine monophosphate (cAMP; as an indicator of phosphodiesterase activity) were measured in skeletal muscle, and interstitial concentrations of histamine (as an indicator of mast cell release) were measured in skin. In muscle, reversed microdialysis with milrinone led to a dose-dependent increase in interstitial cAMP concentrations (n = 8), whereas no significant effect on cAMP was observed for theophylline versus placebo (1.63 +/- 0.53 nmol/L; n = 6), even at local concentrations exceeding those attained after therapeutic doses. In skin, reversed microdialysis with compound 48/80 increased interstitial histamine concentration dose dependently versus placebo (5.99 +/- 2.74 nmol/L; n = 10). From our experiments in human skeletal muscle and skin, we concluded that microdialysis was a suitable technique for the characterization of in vivo drug response at the relevant target site. Extension of these measurements to several other human tissues is readily feasible.
Müller
M
M
Department of Clinical Pharmacology, University of Vienna, Austria.
Burgdorff
T
T
Jansen
B
B
Singer
E A
EA
Agneter
E
E
Dorner
G
G
Brunner
M
M
Eichler
H G
HG
D000328:Adult; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism; D006801:Humans; D008297:Male; D017551:Microdialysis / Q000379:methods*; D020105:Milrinone; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology*; D003189:p-Methoxy-N-methylphenethylamine / Q000008:administration & dosage / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D003189:p-Methoxy-N-methylphenethylamine; D006632:Histamine; D013806:Theophylline; D000242:Cyclic AMP; D020105:Milrinone