S. Sato et al., PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF L-DOPA IN RATS .1. PHARMACOKINETIC ANALYSIS OF L-DOPA IN RAT PLASMA AND STRIATUM, Biological & pharmaceutical bulletin, 17(12), 1994, pp. 1616-1621
The purpose of this investigation was to quantitatively describe the p
harmacokinetics of exogenous and endogenous L-dopa in plasma and the s
triatum using a basic physiological model, and to determine the appare
nt metabolism clearance from L-dopa to dopamine in the striatum. Male
Wistar rats were used in this study. The time courses of L-dopa concen
trations in plasma and the striatum were determined before and after t
he rapid i.v. injection of 10, 50 and 100 mg/kg. Plasma and striatum s
amples were obtained over 480 min (17 time points) from different grou
p of animals and then assayed by HPLC-ECD. The endogenous L-dopa conce
ntration in plasma before drug administration was 2.1 +/- 0.6 mg/l. Th
e exogenous L-dopa concentration declined biexponentially with time af
ter drug injection. The total clearance of exogenous L-dopa in plasma
was 3.13(l/h)/kg. The production rate constant of endogenous L-dopa in
plasma was 6.59(mg/h)/kg. The value of the production rate constant o
f endogenous L-dopa in plasma could be calculated by the multiplicatio
n of the total clearance of L-dopa and the endogenous L-dopa concentra
tion in plasma before drug injection. The pharmacokinetics of endogeno
us and exogenous L-dopa in plasma could be described quantitatively by
a two compartment model which included the production rate constant o
f endogenous L-dopa. The time course of L-dopa concentrations in the s
triatum was analyzed on a hybrid model in which the striatum compartme
nt is independently connected,vith the plasma compartment by the appar
ent diffusion clearance. The striatum compartment has two apparent fir
st-order clearance terms, one from the plasma to the striatum, the oth
er from the striatum to the outside of the striatum, including the met
abolism clearance from L-dopa to dopamine in the striatum. The time co
urse of L-dopa concentration in the striatum could be described by the
basic physiological model, and the apparent metabolism clearance from
L-dopa to dopamine in the striatum could be determined by the basic p
hysiological model.