SIMULTANEOUS IN-VIVO MICRODIALYSIS IN PLASMA AND SKELETAL-MUSCLE - A STUDY OF THE PHARMACOKINETIC PROPERTIES OF LEVODOPA BY NONCOMPARTMENTAL ANALYSIS

This in vivo study compared the pharmacokinetics of intravenously (iv) administered levodopa (L-dopa) in plasma and skeletal muscle. For this purpose, a single iv dose of L-dopa (25 mg/kg) was given to an anesthetized beagle dog, and L-dopa as well as its O-methyl metabolite, 3-O-methyldopa (3-OMD), were monitored in plasma and skeletal muscle simultaneously by microdialysis. The plasma and muscle dialysates were continuously collected during a 3-h period after the iv administration of the drug. The pharmacokinetic variables were then compared in both tissues with noncompartmental modeling. The mean maximum concentration (C-max) for L-dopa in plasma was 173.10 +/- 9.85 ng/mL, whereas in skeletal muscle extracellular fluid, it was 14.56 +/- 2.27 ng/mL. The area under the curve of concentration versus time from time zero to infinity (AUC(0-->inf)) values for L-dopa were 20 times higher in plasma compared with muscle. The difference in half-life between the two tissues probably indicated the large contribution of the distribution phase in either or both tissues over the 3-h time interval. Interestingly enough, the AUC(0-->3h) values for 3-OMD were within the same range in both tissues. These data demonstrated that over a period of 3 h, no distribution equilibrium for L-dopa was reached over the two tissues. The very low L-dopa/3-OMD ratios suggested that, in contrast to L-dopa, 3-OMD is accumulating in skeletal muscle. Whether these findings have any implication for the therapeutic response to L-dopa in Parkinson's disease remains to be determined.