Pharmacodynamic aspects of drug administration. Tolerance development

In the present investigations continuous intraduodenal infusion of levodopa has been given to patients with advanced Parkinson's disease during 6 months (seven patients) and 2.5 years (two patients). The plasma concentration and the effects on motility have been studied at the start, at 3 and 6 months and after 2.5 years. The individually titrated steady state plasma concentrations ( C ss) for satisfactory mobility was found to be decreased by the time, and already after 1 month of intraduodenal infusion C ss was decreased by about 50%. The obtained data indicate an increased sensitivity with time to levodopa, interpreted as a consequence of disappearing tolerance by the controlled drug delivery. Blood pressure and heart rate were studied in spontaneous hypertensive rats during continuous administration of l-propranolol. A maximum reduction in heart rate of about 20% was seen, but no tolerance was observed. All animals showed, however, rebound effects that were at a maximum 3 days after drug withdrawal. Different PK/PD models have been fitted to the data and an indirect effect model seems to be the most appropriate.