Metabolism of 3,4-dihydroxyphenylalanine (l-DOPA) in human subjects

Goodall, McC.; Alton, Harold

doi:10.1016/0006-2952(72)90392-9

Cited by 62 publications

(16 citation statements)

References 27 publications

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“…Finally, these reactions can proceed sequentially, resulting in the formation of homovanillic acid, which is the final end-product of dopa and dopamine metabolism. In all, 35 metabolites of levodopa have been identified in man (Goodall & Alton 1972). 7l.6% of radioactivity administered as 14C-dopa to normal subjects is recovered in the urine in 24 hours, 80% in 120 hours.…”

Section: Metabolic Pathwaysmentioning

confidence: 98%

“…11 % of the dose is recovered as metabolites of dopa itself or 3-0-methyldopa, 64% as dopamine or its metabolites, and 5% as noradrenaline or its metabolites. Thus, at least 80% of administered levodopa enters the catecholamine pathways, as judged from the pattern of metabolite excretion (Goodall & Alton 1972). The remainder presumably ends up in melanin pigment or being transaminated (CaIne et al 1969), with the carbon skeleton entering pathways of intermediary metabolism.…”

Section: Metabolic Pathwaysmentioning

confidence: 99%

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Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

Cedarbaum

1987

Clinical Pharmacokinetics

172

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Of the neurological disorders, none can claim a battery of therapeutic agents based upon as rational a pharmacology as can Parkinson's disease. In this review, the clinical pharmacokinetics of the major classes of anti-Parkinsonian drugs is discussed. Although they are the oldest drugs in the anti-Parkinsonian armamentarium, little pharmacokinetic data are available regarding the anticholinergic and antihistaminic agents. Based on elimination half-lives of 10 to 18 hours, most could probably be effectively given on a twice-daily schedule. Amantadine is unique among anti-Parkinsonian agents both in lacking a clearly defined mechanism of action and in being eliminated from the body exclusively by renal excretion of unchanged drug. Thus the normal decline of renal function in the elderly Parkinsonian population becomes an important factor in avoiding potential drug toxicity. The pharmacokinetics and pharmacodynamics of levodopa are complex. Since it is an amino acid, it follows metabolic pathways and must compete for absorption and brain uptake with a number of large neutral amino acids. It has a short elimination half-life and, as Parkinson's disease progresses, the brain loses its capacity to store the drug and becomes dependent in a moment-to-moment fashion on plasma levodopa concentrations, creating therapeutic response fluctuations in over 50% of patients. Pharmacokinetic considerations in the management of these response fluctuations are discussed. The newest class of anti-Parkinsonian agents are the direct acting dopamine receptor agonists. These drugs, all derivatives of ergot, have more prolonged durations of anti-Parkinsonian action than levodopa. However, other than bromocriptine, clinical experience with members of this class of drugs is still limited.

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Section: Metabolic Pathwaysmentioning

confidence: 98%

Section: Metabolic Pathwaysmentioning

confidence: 99%

Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

Cedarbaum

1987

Clinical Pharmacokinetics

172

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“…These are decarboxylation to dopamine, O-methylation to 3-methoxytyrosine and transamination to 3,4 dihydroxyphenyl pyruvic acid ( Figure 1). 2,3 Therapeutic manoeuvres have been aimed at inhibition of peripheral decarboxylation (e.g. by carbidopa or benserazide) and of O-methylation (e.g.…”

Section: Introductionmentioning

confidence: 99%

Parkinson's disease: the effect of L-dopa therapy on urinary free catecholamines and metabolites

Davidson¹,

Grosset

2007

Ann Clin Biochem

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AddressesBackground L-dopa is an important antiparkinsonian drug. It is a precursor of dopamine and the other catecholamines. Potentially, administration of L-dopa could lead to increased urinary excretion of catecholamines and their metabolites to abnormal amounts. The current study aimed to determine these excretions in patients with Parkinson's disease (PD) receiving L-dopa compared with suitable controls. This is the first assessment of the effect of exogenous administration of L-dopa on urinary free metadrenalines.Methods Using one-way analysis of variance (ANOVA), urine catecholamines and metabolites, expressed as mmol per mole creatinine, were compared in: patients with PD who were receiving L-dopa; patients with PD but not receiving L-dopa; and patients without PD who were being investigated for the presence of phaechromocytoma but were found not to have the disease.Results Significantly higher values for urinary dopamine, homovanillic acid, free normetadrenaline and free metadrenaline were found in patients with PD receiving L-dopa compared with the other two control groups. In all the patients with PD, these four analytes were significantly correlated with daily dose of L-dopa.Conclusion L-dopa therapy can result in production of false positives for urinary excretion of dopamine, homovanillic acid, free normetadrenaline or free metadrenaline and thereby decrease the diagnostic value of these measurements in identifying phaeochromocytoma and related tumours.

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“…4-S-CP and 4-S-CAP require a catalytic amount of dopa for optimal mammalian tyrosinase activity. The majority of L-dopa, when administered intravenously, was decarhoxylated (approximately 64%) and metabolized into catecholamine pathway [32]. To enhance the potential anti-melanoma effect and to inhibit the decarboxylation of these two synthetic compounds, L-dopa and antidecarboxylase (carbidopa) were given simultaneously.…”

Section: In Vivo and In Vitro Selective Accumulation Of Cp And Cap Inmentioning

confidence: 99%

Exploitation of Pigment Biosynthesis Pathway as a Selective Chemotherapeutic Approach for Malignant Melanoma.

Jimbow¹,

Iwashina²,

Alena³

et al. 1993

J Invest Dermatol

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Human malignant melanoma represents a difficult therapeutic challenge to both medical scientists and practicing physicians. However, the biologic uniqueness of the tumor may provide opportunities for exploitation in therapeutics. This study proposed to undertake a systemic approach to the chemotherapy of malignant melanoma based upon the uniqueness of pigment-cell metabolic pathway pertaining to conversion of tyrosine and dopa with subsequent formation of melanin by tyrosinase and its related enzymes. The sulphur homologue of tyrosine, cysteinylphenol (CP), its amine derivative, cysteaminylphenol (CAP), and their N-acetyl and alpha-methyl derivatives have been synthesized and tested in in vivo and in vitro melanocytotoxicity and antimelanoma effects. These phenolic thioethers (PTEs) and phenolic thioether amine (amides) (PTEAs), which are substrates of tyrosinase, showed significant cytotoxicity that is selective to melanocytes and melanoma cells. Most previous attempts to impair the melanin pathway as a therapeutic strategy have been of limited success because they have been directed to catecholic compounds that are unstable and insufficient in lethality at physiologically tolerable doses. By contrast, our approach relies on phenolic compounds, PTEs and PTEAs, which are more stable than catechols and become toxic only after oxidation by tyrosinase. We found PTEA as the most promising agent for the future development of chemotherapeutic agents. The possible biologic, chemical, and pharmacologic reactions of these synthetic compounds within the melanoma cells are studied and discussed.

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Metabolism of 3,4-dihydroxyphenylalanine (l-DOPA) in human subjects

Cited by 62 publications

References 27 publications

Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

Parkinson's disease: the effect of L-dopa therapy on urinary free catecholamines and metabolites

Exploitation of Pigment Biosynthesis Pathway as a Selective Chemotherapeutic Approach for Malignant Melanoma.

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