Discussion U.K. Rinne, Turku: May I introduce some statistics concerning the development of these fluctuations in drug response, as obtained in a long follow-up study? The incidence of these fluctuations increases with duration of treatment so that after 3-5 years about one third, after 5 and 7 years about one half, and when one treats these patients for more than 10 years, more than 80% are suffering from fluctations and about 70% of them from end-of-dose deterioration or wearing-off

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... . A. Lees, London: I think one of the strongest arguments for continuing to look at pharmacokinetic factors is their importance in the pathogenesis of wearing-off effects and on-off effects. The data which are coming out from the bromocriptine trials in previously untreated patients are also of interest. One sees therapeutic responses comparable to those seen with L-dopa; but after many years of treatment one still does not see any on-off effects. CD. Marsden, London: I wonder if I could ask Dr. Hardie to comment on his two-compartmental model and discuss what compartments he has in mind and what pharmacokinetic change he would think might be occurring during chronic treatment within these two compartments. R.J. Hardie, London: It is well known that levodopa is distributed widely throughout the body and particularly taken up very rapidly into skeletal muscle in common with other amino acids, and one of the possibilities that might be going on is that when the patient has been dosed chronically, the skeletal muscle compartment might be loaded and it may be that there is back diffusion of levodopa during the falling phase of the plasma curve. A second possibility which has intrigued many workers over the years is that in fact it may not be an anatomical compartment at all, but indeed a chemical compartment. As you know people have attempted to correlate 3-O-methyldopa levels with some form of a therapeutic response, and it has long been postulated by certain workers that demethylation of O-methyldopa might possibly be a further source of sustaining plasma levodopa levels when the orally absorbed material is actually in a declining phase. O-methyldopa is a metabolite present in something like 5 or 10 times the concentration of the parent drug levodopa itself in plasma. Many people have tried to fit in what O-methyl is doing. Unfortunately, of course, there is the compounding problem which, I think, Prof. Da Prada was referring to, namely that O-methyldopa competes 48 Discussion