The metabolism of L‐3–0‐methyldopa, aprecursor of dopa in man

Kuruma, Isami; Bartholini, G.; Tissot, R; Pletscher, A.

doi:10.1002/cpt1971124678

Cited by 61 publications

(24 citation statements)

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“…Therefore high concentrations of 3-OMe dopa may be a contributory factor in the reduced clinical response during long-term therapy. Such antagonism of the clinical response might be partially offset by re-conversion of the metabolite to levodopa, since Kuruma et al (1972) showed that measurable values of levodopa were present in human plasma after administration of 3-OMe dopa. If circulating concentrations of the metabolite gradually rise with chronic therapy, concomitant increases in the formation of levodopa might be partially responsible for the long terminal half-life seen in this study.…”

Section: -Ome Dopamentioning

confidence: 99%

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

Hardie¹,

Malcolm²,

Lees³

et al. 1986

Brit J Clinical Pharma

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We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease. They all showed on‐off fluctuations whilst receiving long‐term treatment with levodopa in combination with a peripheral decarboxylase inhibitor. Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy. Following infusion rates of 32‐80 mg h‐1 (0.5‐1.3 mg kg‐1 h‐1) the plasma concentration associated with optimum therapeutic response lay between 0.3 and 1.6 mg l‐1. There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects. The concentration of 3‐OMe dopa in plasma hardly increased during each day's levodopa therapy. In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10. In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two‐compartment kinetic model. It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on‐ off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response.

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Section: -Ome Dopamentioning

confidence: 99%

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

Hardie¹,

Malcolm²,

Lees³

et al. 1986

Brit J Clinical Pharma

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“…3-O-methyldopa has been observed to be a major metabolite of exogenous L-DOPA in the plasma and brain of both animals and man (Sharpless & McCann, 1971;Kuruma, Bartholini, Tissot & Pletscher, 1972). Studies show that parenterally administered 3-0-methyldopa accumulates in the brain, has a plasma half-life of 15 h, and undergoes demethylation in both rats and man (Bartholini, Kuruma & Pletscher, 1970;Chalmers, Draffan, Reid, Thorgeirsson & Davies, 1971;Kuruma et al, 1972). The possibility that 3-0-methyldopa is a good and stable precursor of dopamine was tested in the treatment of parkinsonism.…”

Section: Introductionmentioning

confidence: 99%

ABSORPTION, METABOLISM AND DISTRIBUTION OF [¹⁴C]‐O‐METHYLDOPA AND [¹⁴C]‐l‐DOPA AFTER ORAL ADMINISTRATION TO RATS

Rivera‐Calimlim

1974

British J Pharmacology

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“…It was also not found to be related to the difference, 2 h post treatment, between active and placebo days in blood pressure, or in plasma levodopa or 3OMD concentration (Table 3). However, in contrast to levodopa, 3OMD has a sufficiently long t,,2 (approximately 15 h, Kuruma et al, 1971) for substitution of a single placebo dose during levodopa maintenance therapy to have little effect on the concentration 2 h later: a negative correlation, reaching significance only at the 5% level, was detected between the treatment effect and the mean of the 3OMD concentration on active and placebo days (rs = 0.59, t = 2.295, d.f. = 10, P < 0.05).…”

Section: Determinants Offoot Strike Index In Healthy Volunteersmentioning

confidence: 99%

Parkinsonian abnormality of foot strike: a phenomenon of ageing and/or one responsive to levodopa therapy?

Hughes

Bowes

Leeman

et al. 1990

Brit J Clinical Pharma

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1 Normally during walking, the heel strikes the ground before the forefoot. Abnormalities of foot strike in idiopathic Parkinson's disease may be amenable to therapy: objective measurements may reveal response which is not clinically apparent. Occult changes in foot strike leading to instability may parallel the normal, age-related loss of striatal dopamine. 2 The nature of foot strike was studied using pedobarography in 160 healthy volunteers, aged 15 to 91 years. Although 16% of strikes were made simultaneously by heel and forefoot, there were no instances of the forefoot preceding the heel. No significant effect of age on an index of normality of foot strikes was detected (P > 0.3). 3 The effect on foot strike of substituting placebo for a morning dose of a levodopa/ carbidopa combination was studied in a double-blind, cross-over trial in 14 patients, aged 64 to 88 years, with no overt fluctuations in control of their idiopathic Parkinson's disease in relation to dosing. On placebo treatment there was a highly significant (P = 0.004) reduction in the number of more normal strikes, i.e. heel strikes plus simultaneous heel and forefoot strikes. The effect appeared unrelated to the corresponding difference between active and placebo treatments in plasma concentration of levodopa or a metabolite of long half-time, 3-0-methyldopa (30MD). However, it correlated negatively (P < 0.05) with the mean of the 3OMD concentrations. 4 It appears that some abnormalities of foot strike due to Parkinson's disease are reversible. Employing test conditions, designed to provoke abnormalities of foot strike, might be useful in screening for pre-clinical Parkinson's disease.

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The metabolism of L‐3–0‐methyldopa, aprecursor of dopa in man

Cited by 61 publications

References 0 publications

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

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

ABSORPTION, METABOLISM AND DISTRIBUTION OF [¹⁴C]‐O‐METHYLDOPA AND [¹⁴C]‐l‐DOPA AFTER ORAL ADMINISTRATION TO RATS

Parkinsonian abnormality of foot strike: a phenomenon of ageing and/or one responsive to levodopa therapy?

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The metabolism of L‐3–0‐methyldopa, aprecursor of dopa in man

Cited by 61 publications

References 0 publications

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

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

ABSORPTION, METABOLISM AND DISTRIBUTION OF [14C]‐O‐METHYLDOPA AND [14C]‐l‐DOPA AFTER ORAL ADMINISTRATION TO RATS

Parkinsonian abnormality of foot strike: a phenomenon of ageing and/or one responsive to levodopa therapy?

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ABSORPTION, METABOLISM AND DISTRIBUTION OF [¹⁴C]‐O‐METHYLDOPA AND [¹⁴C]‐l‐DOPA AFTER ORAL ADMINISTRATION TO RATS