Plasma levodopa

Rabey JM, Vered Y. Shabtai H, Graff F, Korczyn AD. (1992). Improvement of parkinsonian features correlate with high plasma levodopa values after broad bean (Vicia faba) consumption. J Neurol Neurosurg Psychiatry. 55(8) 725-27. 

Pharmacology These agents are used in combination because carbidopa inhibits decarboxylation of levodopa and makes more levodopa available for transport to the brain. There is less variation in plasma levodopa levels than with the conventional formulation. However, the extended-release form is less systemically bioavailable (70% to 75%) and may require increased daily doses to achieve the same level of symptomatic relief. 

The reason for dyskinesias in some patients, however, may be far more complex. Certain patients, for example, may exhibit dyskinesias when plasma levodopa levels are rising or falling, or even when plasma levels are at a minimum.66 There is evidently an intricate relationship between the basal ganglia neurons that continue to release or respond to dopamine and the pharmacologic replacement of dopamine through levodopa therapy. Dyskinesias may actually be the result of functional and structural adaptations of these neurons caused by periodic fluctuations in dopamine influence supplied from exogenous sources (levodopa).7,68... 

Quantification. Gas Chromatography. In plasma levodopa and dopamine, FCD—Y. Mizuno, Clinica chim. Acta, 1977, 74, 11-19. 

High Pressure Liquid Chromatography. In plasma levodopa and 3,4-dihydroxyphenylaceticacid, sensitivity 1 ng/ml, electrochemical detection—F. Nissinen and J. Taskinen, J. Chromat., 1982, 231 Biomed. AppL, 20, 459-462. In urine levodopa and... 

Following single oral doses of 1.5 g to 42 subjects, peak plasma-levodopa concentrations averaged about 1 pg/ml at 1 to 2 hours but there was a tenfold variation in peak concentrations. Peak plasma concentrations of 3-0-methyldopa of about 1.5 pg/ml were attained in about 4 hours and concentrations of HVA in the cerebrospinal fluid reached a maximum of about 0.15 j.g/ml in 8 hours (S. Bergmann et al., Br. J. din. Pharmac., 1974, 7,417 24). 

Dyskinesia comprises involimtary writhing movement of the face and limbs that may be biphasic (occurring at the start and end of motor response) or develop at the time of the maximum plasma levodopa concentration. They respond initially to reducing the dose of levodopa but at the cost of bradykinesia and as time peisses there is progressively less scope to obtain benefit without unwanted effects. 

The on-off effect should be differentiated from the wearing-off or end-of-dose response. Wearing off is clearly related to the dosage and blood level of levodopa. As the disease progresses and the number of nigral striatal neurons decreases, less dopamine can be stored in the striatum. This necessitates the constant replenishment of levodopa from the blood, so that the bioavailability of plasma levodopa becomes an important factor. 

The small intestine is the major site of absorption for levodopa, and delayed gastric emptying appears to result in low plasma levodopa levels, probably because levodopa can be metabolised in the stomach. In theory, antacids may reduce gastric emptying time, and increase levodopa absorption. It is not known why antacids reduced absorption from the slow-re-lease preparation. ... 

The small intestine is the major site of absorption for levodopa. Delayed gastric emptying, which can be caused by antimuscarinics, appears to result in lower plasma levodopa levels and thus lower brain levodopa levels. This is because the gastric mucosa has more time to metabolise the levodopa to dopamine and theicfoic less is available for absorption. ... 

A study in 20 patients with Parkinson s disease taking levodopa/carbidopa found that overall there was no difference in plasma levodopa levels after bromocriptine was also taken, although some patients had either significant elevations or significant reductions in levels. However, the only adverse clinical change found was an increase in dyskinesias in the patients with elevated levodopa levels. An earlier study found no pharmacokinetic interaction between levodopa/carbidopa and bromocriptine, but it should be noted that this was a single-dose study and may not reflect long-term concurrent use. ... 

A study in patients with Parkinson s disease taking levodopa found that if taken with a meal, the mean absorption of levodopa from the gut and the peak plasma levels were redueed by 27 and 29% respectively, and the peak plasma level was delayed by 34 minutes. Another study found that peak plasma levodopa levels were reduced if the levodopa was taken with food rather than when fasting. ... 

A study found that the clinical response to a constant intravenous infusion of levodopa in 4 patients was unchanged by glycine and tysine but was reduced by phenylalanine, leucine and isoleucine, although the plasma levodopa levels remained unchanged. ... 

Penicillamine can raise plasma levodopa levels in a few patients. This may improve the control of the parkinsonism but the adverse effects of levodopa may also be increased. 

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

These drugs are thought to prolong the effect of levodopa by blocking an enzyme, catechol-O-methyltransferase (COMT), which eliminates dopamine. When given with levodopa, the COMT inhibitors increase the plasma concentrations and duration of action of levodopa... 

Irrespective of whether or not DA can cross the blood-brain barrier it will certainly be destroyed after oral administration by MAO and COMT in the gut and liver before achieving an adequate plasma concentration. Levodopa, by contrast, is not a good substrate for MAO, although metabolised by COMT (Fig. 15.4) and is transported across the gut and blood-brain barrier. 

Unfortunately levodopa (only the levo form of dopa is active) has a very short plasma half-life Vit) of 1 Vi-l hours. Also it is estimated that only 30% of an oral dose reaches the circulation and less than 10% of that gets into the CNS. How, then, can the efficacy of levodopa be improved ... 

These effects could result from the progression of the disease but as they are a feature of levodopa therapy a change in the central response to levodopa or changes in its peripheral kinetics are more likely. The latter does not occur since the maximum plasma concentration, the time to reach it and the plasma half-life are still similar after 10 years of treatment to those achieved initially, although continuous infusion of dopa can smooth out the swings. 

Attention has been given to the possibility that some of the above motor effects may arise from a metabolite of levodopa. The prime suspect is OMD which has a half-life of some 20 hours and reaches plasma concentrations three- to fourfold those of dopa. Suggestions that it may compete with dopa for entry across the blood-brain barrier or act as a partial agonist (effective antagonist) have not been substantiated experimentally although it does reduce DA release from rat striatal slices. Also if free radical production through deamination of DA is neurotoxic (see below) then this would be increased by levodopa. 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

Pharmacology Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), which alters the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor (such as carbidopa), plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. 

Levodopa is rapidly absorbed when given orally and peak plasma level is... 

When used along with levodopa, the plasma half life of levodopa is prolonged and dose may be markedly reduced. Also the most common side effect i.e. nausea and vomiting are not prominent and cardiac complications are minimized. It has no effect on involuntary movements, behavioral abnormalities and postural hypotension. 

The pharmacologic effects of tolcapone and entacapone are similar, and both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. The half-life of both drugs is approximately 2 hours, but tolcapone is slightly more potent and has a longer duration of action. Tolcapone is taken in a standard dosage of 100 mg three times daily some patients require a daily dose of twice that amount. By contrast, entacapone (200 mg) needs to be taken with each dose of levodopa, up to five times daily. 

Levodopa usually increases plasma growth hormone concentrations (594). 

Galea-Debono A, Jenner P, Marsden CD, Parkes JD, Tarsy D, Walters J. Plasma DOPA levels and growth hormone response to levodopa in parkinsomism. J Neurol Neurosurg Psychiatry 1977 40(2) 162-7. 

Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, de Mari M, Livrea P. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson s disease patients. Mov Disord 2005 20 69-72. 

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