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PubMed1999

NMSP binding to dopamine and serotonin receptors in MPTP-induced parkinsonism: relation to dopa therapy.

We tested the hypothesis that N-methylspiperone binding to dopamine D2 receptors must be reduced when L-dopa therapy of parkinsonism augments the binding of dopamine to the receptors and improves the clinical state expressed by the Hoehn & Yahr stage. A patient with MPTP-induced parkinsonism underwent two positron emission tomographic studies of the D2-like dopamine receptors with N-[11C]methylspiperone (NMSP). The first study took place 3 days after cessation of the L-dopa medication, the second 5 days after its resumption. Noticeable clinical deterioration occurred during both studies, consistent with significant dopamine receptor blockade by NMSP and elevated NMSP binding in both scans. The dopa treatment did not reduce the NMSP binding. On the contrary, the rate of binding of NMSP (k3) was increased on-dopa, compared to off-dopa. The increase was consistent with the slightly greater dopamine receptor density estimated after resumption of the dopa therapy. The NMSP binding to serotonin receptors suggested lower synaptic serotonin on-dopa than off-dopa. The results are consistent with negative correlation between the Hoehn & Yahr stage and the amount of dopamine bound to dopamine D2 receptors. Low synaptic serotonin may explain the depression seen in some patients on dopa for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1982

Transamination and other metabolic pathways of 3,4-dihydroxyphenylpyruvic acid in rats when simultaneously administered with L-dopa.

In the rat, 3,4-dihydroxyphenylpyruvic acid (DHPPA) was shown to be transaminated to L-dopa when administered orally concomitantly with L-[3H]dopa. As much as 40% of the serum L-dopa and brain dopamine was shown to be formed via transamination. Moreover, it was shown that DHPPA also caused a so-called L-dopa-sparing effect, i.e. more administered L-dopa reached the circulation and consequently more dopamine reached its target than after administration of L-dopa alone. This effect might be due to an inhibition of the deamination of L-[3H]dopa, since in this case the equilibrium of the transamination reaction will be forced into the L-dopa-forming direction. After administration of [14C]DHPPA alone and together with L-dopa, no differences in the absorption and distribution of radioactivity were found.

Animals↗
PubMed1991

Peripheral pharmacokinetic handling and metabolism of L-dopa in the rat: the effect of route of administration and carbidopa pretreatment.

The effect of carbidopa (L-alpha-methyldopa hydrazine; 25 mg kg-1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxyphenylalanine (L-dopa; 50 mg kg-1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-infinity) after L-dopa i.a. and increased AUC0-infinity after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

A pulmonary formulation of L-dopa enhances its effectiveness in a rat model of Parkinson's disease.

The efficacy of oral L-dopa becomes problematic with the progression of Parkinson's disease, due in large part to a lost ability to accommodate L-dopa's inherently poor pharmacokinetics. Pulmonary delivery represents a novel approach to reducing this problem. L-dopa was formulated into inhalable (Alkermes AIR) particles, and its pharmacokinetics and pharmacodynamics compared with those of an oral formulation. Pulmonary administration of L-dopa (2 mg) to rats resulted in a rapid elevation of plasma levels (C(max) = 4.8 +/- 1.10 microg/ml at 2 min), whereas oral administration of L-dopa produced a much delayed and lower C(max) (1.8 +/- 0.40 microg/ml at 30 min). In a rat model of Parkinson's disease (unilateral 6-hydroxydopamine lesion), the pulmonary formulation of L-dopa (0.5-2.0 mg) yielded more rapid and robust elevations in striatal L-dopa, dopamine, and dihydroxyphenylacetic acid levels, as well as 2.5 to 3.7 times as many c-fos-expressing striatal neurons. Moreover, motor function was significantly improved by 10 min after administration, with peak improvements occurring within 15 to 30 min. In contrast, considerably higher doses (6.8-10 mg) of orally administered L-dopa took over three times longer to produce similar effects. These results suggest that an inhalable formulation of l-dopa has superior pharmacokinetic properties and may provide patients with a more effective form of rescue therapy as well as being a reliable adjuvant or replacement for first-line oral therapy.

Administration, Inhalation↗
PubMed2000

DOPA, dopamine, and DOPAC concentrations in the rat gastrointestinal tract decrease during fasting.

The aim of the present study was to test the hypothesis that 3, 4-dihydroxyphenylalanine (DOPA) and dopamine (DA) in the gastrointestinal tract are to a large extent of exogenous origin and derived from food. Tissue concentrations of norepinephrine (NE), epinephrine (Epi), DA, DOPA, and 3,4-dihydroxyphenylacetic acid (DOPAC), as measured by reverse-phase HPLC with electrochemical detection, were studied in fed and 4-day-fasted Wistar rats as well as in sympathectomized and adrenodemedullated rats. Sympathectomy and adrenal demedullectomy decreased tissue concentrations of NE and Epi, respectively, but had no effect on the level of tissue DOPA. Large amounts of DOPA and DA were present in the gastrointestinal tract. Fasting decreased DOPA and DA in the stomach and DOPA concentrations in the quadriceps muscle but no concentrations in other organs. DOPAC in the heart decreased both in response to sympathectomy and to fasting, whereas DOPAC decreased in plasma after fasting and in skeletal muscle after sympathectomy. We conclude that the food content of DOPA and DA is of major importance for the metabolism of DA and, thus, for the dopamine-sulfate content in the gastrointestinal tract and in plasma. The decrease in muscle DOPA after fasting may be explained by less insulin being available during fasting for stimulation of DOPA uptake in the muscle depot. DOPAC in the organism seems to be of a dual origin, derived partly from DA in the food and partly from DA synthesized in sympathetic nerves.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Molecular modulation of inward and outward apical transporters of L-dopa in LLC-PK(1) cells.

The present study examined the nature of the apical inward and outward L-3,4-dihydroxyphenylalanine (L-dopa) transporters in LLC-PK(1) cells and whether protein kinases differentially modulate the activities of these transporters. The apical inward transfer of L-dopa was promoted through an energy-dependent and sodium-insensitive transporter (Michaelis constant = 38 microM; maximum velocity = 2608 pmol. mg protein(-1). 6 min(-1)). This transporter was insensitive to N-(methylamino)-isobutyric acid but competitively inhibited by 2-aminobicyclo(2,2, 1)-heptane-2-carboxylic acid (BHC; IC(50) = 251 microM). Modulators of protein kinase A (cAMP, forskolin, IBMX, and cholera toxin), protein kinase G (cGMP, zaprinast, LY-83583 and sodium nitroprusside), and protein kinase C (phorbol 12,13-dibutirate and chelerythrine) failed to affect the accumulation of L-dopa. The Ca(2+)/calmodulin inhibitors calmidazolium and trifluoperazine inhibited L-dopa uptake (IC(50) of 72 and 55 microM, respectively). The inhibitory effect of calmidazolium on the accumulation of L-dopa was of the noncompetitive type. The organic anion inhibitor DIDS, but not p-aminohippurate, and the protein tyrosine kinase (PTK) inhibitor genistein significantly increased L-dopa accumulation, which was mainly due to inhibition of apical outward transfer of L-dopa. It is concluded that LLC-PK(1) cells take up L-dopa over the apical cell border through the L-type amino acid transporter, which appears to be under the control of Ca(2+)-calmodulin-mediated pathways. The apical outward transfer of L-dopa may be promoted through a DIDS-sensitive transport mechanism and appears to be under the tonic control of PTK.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2003

BIA 3-202, a novel catechol-O-methyltransferase inhibitor, reduces the peripheral O-methylation of L-DOPA and enhances its availability to the brain.

The present study aims at determining the effects of the catechol-O-methyltransferase (COMT) inhibitor BIA 3-202 [1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone] upon levels of L-3,4-dihydroxyphenylalanine (L-DOPA) and metabolites in peripheral circulation (jugular vein), whole brain, and striatal microdialysates in rats orally treated with L-DOPA plus benserazide. A low dose (3 mg/kg) of BIA 3-202 was relatively selective to inhibit liver COMT, being devoid of major significant inhibitory effects upon brain COMT. By contrast, a high dose (30 mg/kg) of BIA 3-202 markedly inhibited liver and brain COMT. BIA 3-202 (3 and 30 mg/kg) reduced the L-DOPA-induced rise of 3-O-methyl-L-DOPA in the peripheral circulation (jugular vein), brain tissue, and striatal dialysate, but failed to increase the levels of dopamine in striatal dialysates despite the increase in dopamine brain levels. However, the changes in brain levels of L-DOPA, 3-O-methyl-L-DOPA, and dopamine and in striatal dialysate levels of L-DOPA and 3-O-methyl-L-DOPA, obtained with 3 mg/kg BIA 3-202, were not different from those obtained with 30 mg/kg BIA 3-202. In conclusion, inhibition of peripheral COMT by BIA 3-202 may suffice to improve the availability of L-DOPA to the brain.

Acetophenones↗
PubMed1976

Effects of long-term L-dopa therapy on carbohydrate metabolism in patients with Parkinson's disease.

Carbohydrate metabolism and insulin secretion were investigated in 26 patients with Parkinson's disease before and during L-dopa treatment. Oral glucose tolerance tests were performed on 13 patients treated with L-dopa alone and on 7 patients treated with L-dopa combined with Carbidopa. Intravenous glucose tolerance tests were performed on additional 6 patients treated with L-dopa alone. Results indicate that chronic L-dopa administration does not modify glucose metabolism. It was observed only a significant decrease of insulin secretion after oral glucose in the early phase (15th day) of treatment with L-dopa alone. This temporary effect may be related to the peripheral conversion of L-dopa to dopamine since insulin secretion during combined therapy was normal. The mechanism by which L-dopa transiently inhibits insulin release is not clear. Perhaps the oral administration of L-dopa alone causes an alteration in some gastrointestinal functions which are involved in the handling of oral glucose.

Adult↗
PubMed1996

The adrenal glands as suppliers of plasma L-Dopa and sources of urinary dopamine.

Dopamine (DA) is a natriuretic hormone synthesized in the kidneys by conversion of filtered 3,4-dihydroxyphenylalanine (L-Dopa), and is activated during hypervolaemia and increased dietary sodium intake. The natriuretic activity of endogenous DA is controversial, however, and the regulation of renal DA synthesis has yet to be explained. It has been suggest that the adrenals may be major suppliers of plasma L-Dopa on the basis of their catecholamine biosynthesis. A study was conducted in rats to elucidate the role of the adrenal glands as dynamic suppliers of L-Dopa to plasma, and thereby as sources of urinary DA. Adrenal venous and systemic arterial plasma concentrations and urinary excretion of L-Dopa, DA and sodium were measured before and during acute isotonic volume expansion (VE; 5% of body weight). One group of animals were acutely adrenalectomized (ADX group) to elucidate the ultimate importance of the adrenals in VE-induced renal sodium and DA excretion. In intact animals, the L-Dopa concentration was 62% higher in adrenal venous than in systemic arterial plasma under control conditions, and 42% higher during VE. The adrenaline concentration was 65 times higher in adrenal venous than in systemic arterial plasma before VE and 56 times higher during VE. The L-Dopa concentration in systemic arterial plasma and the urinary L-Dopa excretion were similar in intact and ADX animals. In intact animals, renal sodium and DA excretion during VE increased more than 13-fold and by 42%, respectively. The corresponding values in ADX animals did not differ from those in the intact animals (more than 14-fold and 36%, respectively). It is concluded that the adrenal glands are only minor suppliers of plasma L-Dopa and minor sources of urinary DA. The regulation of plasma L-Dopa remains to be explained.

Adrenal Glands↗
PubMed2006

Effect of oxidative stress induced by L-dopa on endogenous antioxidants in PC-12 cells.

The mechanism of action of many drugs of abuse involves the dopaminergic pathway. One method of increasing dopamine in brain is by ingestion of L-dopa (3,4-dihydroxy-L-phenylalanine). Interestingly, both dopamine and L-dopa cause oxidative stress which is also a factor in drug-induced damage. Oxidative stress can be reduced by the antioxidant activities of vitamins C (ascorbate) and E (tocopherols). However, the interactions between L-dopa and tocopherols and ascorbate are not well understood. In this article, PC-12 cells (as models of neurons) were cultured for 21 hours with ascorbate (400 microM) and/or alpha tocopherol (25 microM) and in the presence or absence of L-dopa (250 microM). After incubation, cells were harvested and analyzed for the various biochemical components by HPLC. As expected, the addition of L-dopa resulted in an almost threefold increase in cellular dopamine content. Addition of alpha tocopherol resulted in marked increase in cellular tocopherol. Similarly, addition of ascorbate substantially increased its cellular concentration. These increases were strongly attenuated by the presence of L-dopa in the medium. The data indicate that: (a) the uptake systems for ascorbate and tocopherols in these cells are inhibited by L-dopa and/or (b) L-dopa treatment causes an increase in the rate of utilization of the two nutrients. Thus L-dopa modulates the cellular dynamics of ascorbate and tocopherol altering cellular antioxidant protection.

Animals↗
PubMed2007

Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography as a tool to localize an insulinoma or beta-cell hyperplasia in adult patients.

CONTEXT AND OBJECTIVE: Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) is a promising method in localizing neuroendocrine tumors. Recently, it has been shown to differentiate focal forms of congenital hyperinsulinism of infancy. The current study was set up to determine the potential of 18F-DOPA PET in identifying the insulin-secreting tumors or beta-cell hyperplasia of the pancreas in adults. PATIENTS AND METHODS: We prospectively studied 10 patients with confirmed hyperinsulinemic hypoglycemia and presumed insulin-secreting tumor using 18F-DOPA PET. Anatomical imaging was performed with computed tomography (CT) and magnetic resonance imaging (MRI). All patients were operated on, and histological verification was available in each case. Semiquantitative PET findings in the pancreas using standardized uptake values were compared to standardized uptake values of seven consecutive patients with nonpancreatic neuroendocrine tumors. RESULTS: By visual inspection of 18F-DOPA PET images, it was possible in nine of 10 patients to localize the pancreatic lesion, subsequently confirmed by histological analysis. 18F-DOPA uptake was enhanced in six of seven solid insulinomas and in the malignant insulinoma and its hepatic metastasis. Two patients with beta-cell hyperplasia showed increased focal uptake of 18F-DOPA in the affected areas. As compared to CT or MRI, 18F-DOPA PET was more sensitive in localizing diseased pancreatic tissue. CONCLUSION: 18F-DOPA PET was useful in most patients with insulinoma and negative CT, MRI, and ultrasound results. In agreement with previous findings in infants, preoperative 18F-DOPA imaging seems to be a method of choice for the detection of beta-cell hyperplasia in adults. It should be considered for the detection of insulinoma or beta-cell hyperplasia in patients with confirmed hyperinsulinemic hypoglycemias when other diagnostic work-up is negative.

Adult↗
PubMed1978

Carbidopa inhibits the growth hormone- and prolactin-suppressive effect of L-dopa in acromegalic patients.

The plasma GH, PRL, TSH, and dopamine (DA) responses to an infusion of L-dopa were examined in six acromegalic patients before and after pretreatment with carbidopa, a drug which inhibits the peripheral conversion of L-dopa to DA. Carbidopa neither modified baseline DA nor induced changes in baseline GH, PRL, or TSH levels. The drug instead markedly reduced the L-dopa-induced DA rise, an effect which was concomitant to a striking reduction of the suppressive effect of L-dopa on plasma GH and a partial inhibition of the suppressive effect of L-dopa on plasma PRL. TSH levels did not change either after L-dopa alone or L-dopa plus carbidopa. These data demonstrate that in "responder" acromegalics, L-dopa inhibits GH secretion through its peripheral conversion to DA and not via activation of central DA neurotransmission. For the effect of L-dopa on PRL secretion, in addition to a peripheral dopaminergic component, a central component cannot be disregarded.

Acromegaly↗
PubMed1987

Growth hormone inhibitory and stimulatory actions of L-dopa in patients with acromegaly.

It is not clear whether dopamine (DA) has a central stimulating activity on GH secretion in patients with acromegaly, as it does in normal subjects. To clarify this, we compared the GH inhibitory potencies of DA, which does not cross the blood-brain barrier (BBB), and L-dopa or bromocriptine, which do cross the BBB, in 23 patients with acromegaly. Further, we examined the central effects of L-dopa after selectively blocking peripheral (median eminence and pituitary) DA receptors with domperidone (a DA D2 receptor blocker which does not cross the BBB). After the administration of DA (5 micrograms/kg X min, iv, for 90 min), L-dopa (500 mg, orally), or bromocriptine (2.5 mg, orally), the mean plasma GH decrease was greatest after DA [maximum decrement, 71.9 +/- 3.8% (+/- SEM); n = 21] compared to L-dopa (44.1 +/- 5.6%; n = 23; p less than 0.001) or bromocriptine (58.9 +/- 5.0%; n = 20; p less than 0.02). Eleven of these patients received a single infusion of domperidone (0.22 mg/min, iv, for 180 min) or a combination of domperidone and L-dopa. Mean plasma GH levels did not change during domperidone alone. However, plasma GH levels in these patients increased significantly when L-dopa was administered 30 min after the start of domperidone infusion (vs. control study: at 90 min, 137.3 +/- 10.8% vs. 100.2 +/- 3.9%, p less than 0.01; at 120 min, 138.8 +/- 19.7% vs. 106.5 +/- 3.1%, p less than 0.05). In contrast, one patient who had a distinct plasma GH increase in response to the domperidone-L-dopa test had no increase in plasma GH when given L-dopa 30 min after the start of a sulpiride infusion (DA D2 receptor blocker which crosses the BBB; 1.1 mg/min, iv, for 180 min). Unlike GH, plasma PRL responses to domperidone infusion were not modified by the additional administration of L-dopa. These results suggest that in acromegaly, DA has not only direct suppressive effects on the pituitary tumor somatotrophs, but also indirect stimulatory effects via the hypothalamus; therefore, the hypothalamic GH-releasing system is not entirely suppressed by excessive tumor GH secretion.

Acromegaly↗
PubMed2003

Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status.

BACKGROUND: The antiparkinsonian drug L-dopa causes increased cellular synthesis of homocysteine and consequent hyperhomocysteinemia in rats. This effect of L-dopa on plasma homocysteine is accentuated under conditions of impaired homocysteine metabolism such as folate deficiency. OBJECTIVE: To investigate the effect of L-dopa administration and B-vitamin status on plasma homocysteine concentrations in humans with PD. METHODS: Plasma homocysteine, folate, vitamin B(12), and pyridoxal-5'-phosphate (PLP) concentrations were determined in 40 individuals diagnosed with idiopathic PD who were being treated as outpatients at the Boston University Medical Center Neurology Clinic. Twenty of the patients were on L-dopa therapy (treatment group) and 20 were L-dopa-naive (control group). RESULTS: The mean plasma homocysteine concentration was higher in the treatment group than in the controls (p = 0.018). Plasma homocysteine was correlated with plasma folate, vitamin B(12), and PLP concentrations in the treatment group (p <or= 0.007) but not in the controls. CONCLUSION: L-Dopa can cause hyperhomocysteinemia in PD patients, the extent of which is influenced by B-vitamin status. The B-vitamin requirements necessary to maintain normal plasma homocysteine concentrations are higher in L-dopa-treated patients than in those not on L-dopa therapy. B-Vitamin supplements may be warranted for PD patients on L-dopa therapy.

Antiparkinson Agents↗
PubMed1983

Effects of 3-OM-dopa on monoamine metabolism in rat brain.

We studied the effects of 3-methoxy, 4-hydroxy-phenylalanine (3-OM-dopa) on monoamine turnover, L-3-4-dihydroxy-phenylalanine (L-dopa) reversal of catecholamine depletion induced by alpha-methyl-paratyrosine (alpha-MT), and the passage of L-dopa across the blood-brain barrier of the rat brain. 3-OM-dopa did not affect monoamine turnover but interfered with restoration of dopamine levels by L-dopa. In addition, systemic 3-OM-dopa decreased brain uptake of 14C-L-dopa. High 3-OM-dopa blood levels may interfere with the therapeutic response to L-dopa in parkinsonism.

Animals↗
PubMed1990

L-dopa facilitates the release of endogenous norepinephrine and dopamine via presynaptic beta 1- and beta 2-adrenoceptors under essentially complete inhibition of L-aromatic amino acid decarboxylase in rat hypothalamic slices.

In rat hypothalamic slices, L-aromatic amino acid decarboxylase (AADC) was assayed, and the actions of L-DOPA on impulse (2 Hz)-evoked norepinephrine (NE) and dopamine (DA) release were studied under inhibition of AADC. Slices were incubated with L-DOPA, and DA and NE produced by conversion of the precursor were analyzed by high performance liquid chromatography with electrochemical detection (HPLC-ECD). In the slices, the Km and Vmax of AADC were 131 microM and 122 pmol/min/mg protein, respectively. NSD-1015, an AADC inhibitor, caused a noncompetitive type of inhibition, and the K1 value was 0.086 microM. In the presence of 20 microM NSD-1015, which was expected to cause 99.6% inhibition of AADC, L-DOPA (0.01-100 nM) concentration-dependently facilitated the release of NE from the superfused slices, and the L-DOPA (10 nM)-induced facilitation was antagonized by 100 nM ICI 89,406 and 100 nM ICI 118,551, a selective beta 1- and beta 2-adrenoceptor antagonist, respectively. This action of L-DOPA was not modified by 30 microM tropolone, an inhibitor of catechol-O-methyl-transferase. L-DOPA at 0.01-1 nM similarly facilitated the release of DA. A quantitative analysis revealed that the L-DOPA-induced increase in NE and DA release was much higher by a factor of 3 to 4 orders than was the amount of DA and NE converted from L-DOPA. These results add further support to the hypothesis that L-DOPA itself acts as a neuroactive substance in the rat central nervous system.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

L-Dopa-induced sedation: a double-blind cross-over controlled study versus triazolam and placebo in healthy volunteers.

Incidental case reports suggest that some parkinsonian patients treated with dopaminergic drugs complain of drowsiness but few controlled data are available. We compared the sedative effects of L-Dopa (200 mg + 50 mg benserazide, PO), triazolam (0.125 mg) and placebo in a randomized double-blind cross-over design in 22 healthy volunteers pretreated with domperidone (60 mg/day). Drowsiness was assessed using a visual analog scale (VAS), a computerized choice reaction time test (CRT) and an electro-oculogram (EOG). L-Dopa and triazolam induced significant drowsiness, compared to placebo, on VAS, CRT and some EOG parameters. After this first evaluation session, all subjects were chronically treated for 11 days with 600 mg/d of L-Dopa. Drowsiness induced by L-Dopa, triazolam or placebo was then tested again on three consecutive days to assess putative dopaminergic tolerance. After chronic L-Dopa treatment, triazolam-induced sedation remained unchanged while L-Dopa sedative effects were no longer significant except on the VAS, preventing the conclusion that tolerance occurred. These data suggest that an acute dose of L-Dopa induces sedation in L-Dopa-naive subjects. This sedative effect must be considered in clinical practice and when studying the effects of L-Dopa on motor or neuropsychological performance, especially in acute tests.

Adult↗
PubMed1976

Cellular mechanisms of renal tubular transport of I-dopa and its derivatives in the rat: microperfusion studies.

Proximal tubular transport of L-3,4-dihydroxyphenylalanine (L-dopa) and its derivatives were studied in the rat kidney by microperfusion and capillary perfusion techniques in situ. With the use of microperfusion techniques alone, it was found that L-dopa, L-3-methoxy-4-hydroxyphenylalanine, L-tyrosine and L-phenylalanine rapidly disappeared from the perfusate. The rates of reabsorption were calculated to be 2.05 X 10(-12), 2.13 X 10(-12), 6.35 X 10(-12) and 7.14 X 10(-12) mol/cm/sec, respectively. In contrast, L-alpha-methyldopa and dopamine were only slightly reabsorbed. The permeability coefficients were calculated to be 0.35 X 10(-4) and 0.21 x 10(-4) and 0.21 x 10(-4) cm/sec, respectively. The rate of reabsorption of L-dopa was greatly reduced in the presence of L-phenylalanine in the perfusate, but was not affected by D-dopa. With the stop-flow microperfusion technique with simultaneous capillary perfusion, the zero net flux transtubular concentration difference (deltaC) of labeled dopa was measured. When the initial concentration of 2 mM labeled L-dopa was perfused, the luminal concentration fell to a plateau level of 1.5 mM after a contact time of 20 seconds; i.e., deltaC was 0.5 mM. The net flux was much less than the efflux, suggesting the presence of a secretory or passive back flux of L-dopa. The deltaC of L-dopa was not influenced by the decarboxylase inhibitor, MK-486, and monoamine oxidase inhibitor, pheniprazine, but was significantly reduced by NaCN. Thus the reabsorption of L-dopa in the proximal convoluted tubule is an active process with great structural specificity.

Absorption↗