CONCENTRATION-EFFECT RELATIONSHIP FOLLOWING LEVODOPA/CARBIDOPA ADMINISTRATION TO ON-OFF PARKINSONIAN-PATIENTS

An effect model is proposed for the prediction of individual motor response in ''on-off'' parkinsonian patients following a single-dose administration of levodopa/carbidopa. The process does not involve any iterative method (in order to minimize hysteresis). For an examination of the model, previously published data of Deleu et al. are used. Following administration of a duodenal bolus of the drug to on-off responders, individual motor score is linearly related to drug concentration in the effect compartment. Linear transformation constants were fairly similar in the four patients examined. If this behavior is generally the case, individual motor response can be predicted from plasma concentration following administration of a duodenal bolus to on-off patients. Following oral administration, a linear relationship between motor score and levodopa effect compartment concentration was found in one patient. With the other patient, a linear relationship persisted for 2 hours only following drug administration. Later, an unpredictable decrease in response was observed. This decrease was unrelated to (the calculated) drug concentration in the effect compartment. Following administration of a duodenal bolus, an on-off responder may react more like a ''wearing-off'' responder by exhibiting less unpredictable fluctuations. The use of a one-compartment open model to describe levodopa pharmacokinetics reveals absorption and elimination rate constants of a comparable magnitude, following an ingestion of a Sinemet tablet. A double flip-flop model is proposed to account for this fact. In order to explain the linear relationship between motor effect and levodopa concentration in the effect compartment, the following relations between enzymatic first-order rate constants, in the effect compartment of on-off responders, are proposed: k(MAO) much greater than k(Decarboxylase), k(COMT) less than or equal to k(MAO), where k(MAO) refers to dopamine as a substrate, whereas k(Decarboxylase) and k(COMT) refer to levodopa. The above relations between rate constants imply also that [dopamine] much less than [levodopa] in the effect compartment following levodopa administration to on-off responders.