The effect of carbidopa on the pharmacokinetics of intravenously administered levodopa: The mechanism of action in the treatment of parkinsonism

Abstract

The pharmacokinetics of short and long intravenous infusions of levodopa with and without concurrent oral administration of carbidopa was studied in 9 parkinsonian patients. Carbidopa reduced by 50% both the infusion rate required to produce a clinical response and the time required for plasma clearance of levodopa. Using this value for clearance, it is estimated that carbidopa doubles the bioavailability of orally administered levodopa. Carbidopa did not alter the therapeutically effective plasma concentration of levodopa, suggesting that carbidopa does not modify the so-called enzymatic blood-brain barrier. The decline of the plasma levodopa concentration was biphasic; carbidopa modestly increased half-lives of both phases. The apparent volume of distribution was not significantly altered. Carbidopa did not change the duration of the clinical response after the discontinuation of short infusions. From these observations we infer that the therapeutic effects of carbidopa can be attributed to doubling the bioavailability of orally administered levodopa and halving its plasma clearance.

The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson's disease who exhibit on‐off fluctuations.

“…Our findings in common with those of Nutt et al (1985) suggest that the pharmacokinetics in patients whose clinical response is fluctuating may be different from the traditional picture. Six out of the seven subjects in our study exhibited biphasic elimination with a rapid a phase.…”

“…Changes in plasma concentration are summarised in Table 4 and show a large variation between patients in pre-dose (2.3-7.7 ,ug ml-') and plateau values (3.3-7.5 ,ug ml-'), although in each patient (Birkmayer et al, 1973;Morris et al, 1976;Sasahara etal., 1980;Broe etal., 1981) that following a rapid distribution phase elimination of the drug from plasma is essentially a first order process with a relatively short elimination half-life of 0.5-1.0 h. Concurrent therapy with decarboxylase inhibitors is reported (Huebert et al, 1983) to have little effect on the half-life of levodopa, in normal volunteers and patients at an early stage of treatment although plasma concentrations increase because of reductions in the clearance and volume of distribution. A recent report however (Nutt et al, 1985) has suggested there may be a modest increase in half-life in patients on long term therapy.…”

The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa.

“…Indeed, correction of the Vs. for lean body mass reduced the age related differences in both studies. The protein binding of levodopa is negligible (Hinterberger & Andrew, 1972) Nutt et al, (1985) found inconsistent changes in the V of levodopa administered as an infusion (2 h or > 20 h) with and without carbidopa. Kaakkola et al (1985) reported an increase in V when the ratio of oral levodopa to carbidopa was altered from 10:1 to 4:1 (although in this case the calculation of V required assumptions regarding bioavailability).…”

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

“…the bioavailability was 30 % (22,35). By adding an AADC inhibitor (DDI) to every levodopa dose the levodopa available in plasma is increased by 35-80 % in human (35,49,(51)(52)(53)(54). It has been shown that the DDI carbidopa reduces this first-pass metabolism to less than 10 % of the dose absorbed (52).…”