A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats.
OBJECTIVE
To study the PK interaction of L-dopa/benserazide in rats.


METHODS
Male rats received a single oral dose of 80 mg/kg L-dopa or 20 mg/kg benserazide or 80/20 mg/kg L-dopa/benserazide. Based on plasma concentrations the kinetics of L-dopa, 3-O-methyldopa (3-OMD), benserazide, and its metabolite Ro 04-5127 were characterized by noncompartmental analysis and a compartmental model where total L-dopa clearance was the sum of the clearances mediated by amino-acid-decarboxylase (AADC), catechol-O-methyltransferase and other enzymes. In the model Ro 04-5127 inhibited competitively the L-dopa clearance by AADC.


RESULTS
The coadministration of L-dopa/benserazide resulted in a major increase in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa clearance. The compartmental model allowed an adequate description of the observed L-dopa and 3-OMD concentrations in the absence and presence of benserazide. It had an advantage over noncompartmental analysis because it could describe the temporal change of inhibition and recovery of AADC.


CONCLUSIONS
Our study is the first investigation where the kinetics of benserazide and Ro 04-5127 have been described by a compartmental model. The L-dopa/benserazide model allowed a mechanism-based view of the L-dopa/benserazide interaction and supports the hypothesis that Ro 04-5127 is the primary active metabolite of benserazide.
Grange
S
S
PRNS Non-Clinical Drug Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland. susan.grange@roche.com
Holford
N H
NH
Guentert
T W
TW
D000465:Algorithms; D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001545:Benserazide / Q000493:pharmacokinetics* / Q000494:pharmacology; D002138:Calibration; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors; D004347:Drug Interactions; D007275:Injections, Intravenous; D007980:Levodopa / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar
D000978:Antiparkinson Agents; D007980:Levodopa; D001545:Benserazide; D002262:Carboxy-Lyases