Patients with Parkinson's disease (PD) in long-term levodopa therapy often
complain of worsening of motor symptoms in the afternoon and evening. The p
athophysiology of this phenomenon is not known. We evaluated the motor resp
onse to repeated doses of levodopa during a 12-hour period in 52 parkinsoni
an patients (19 de novo, 20 stable, and 13 wearing-off). On the day of the
study, all patients received standard doses of levodopa/carbidopa at 8:00 a
.m., 12:00 noon, and 4:00 p.m. Motor measurements such as lapping test, wal
king time, and tremor score, and blood samples for levodopa and 3-O-methyld
opa (30MD) plasma analysis, were performed hourly. Mean motor scores and ph
armacokinetic data, evaluated for a period of 3 hours after each levodopa d
ose, were compared. In de novo patients, we did not observe diurnal changes
in motor score, whereas a progressive daytime worsening was visible in sta
ble and wearing-off patients. No significant difference in levodopa pharmac
okinetics after each levodopa dose was observed within each patient group,
whereas 30MD plasma levels significantly increased with repeated levodopa a
dministrations. However, no significant correlation between motor scores an
d 30MD plasma levels was observed, suggesting that the diminishing motor re
sponse to afternoon and evening doses of levodopa in patients in long-term
levodopa therapy does nor relate to the pharmacokinetics of the drug. It is
possible that this phenomenon may be an expression of the occurrence of to
lerance to repeated doses of levodopa.