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

Robertson, D. R. C.; Wood, N. D.; Everest, HM; Monks, Kitty; Waller, Derek G.; Renwick, A. G.; George, C. F.

doi:10.1111/j.1365-2125.1989.tb03506.x

Cited by 105 publications

(89 citation statements)

References 30 publications

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“…However, there was no significant difference in GE between PD patients with severe and less severe disease, indicating that other factors than GE influence the levodopa uptake from the GI tract. It has earlier been shown that the absorption of levodopa from the gut is accelerated after long exposure to levodopa (180,181) and that age also seems to affect levodopa uptake since higher levels of levodopa has been seen in older PD patients (49,182). However, in our study neither significant age difference nor any obvious time difference of levodopa treatment was seen in the two PD groups.…”

Section: Discussioncontrasting

confidence: 54%

“…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).…”

Section: Levodopa In the Peripherymentioning

confidence: 99%

“…It is more likely the result of differences in COMT activity between gender (48). Age also seems to affect levodopa availability with higher levels in elder persons (age >65) and decarboxylation is thought to be the age dependent factor (49,50).…”

Section: Levodopa In the Peripherymentioning

confidence: 99%

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

Nord¹

2017

Linköping University Medical Dissertations

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindrin...

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Section: Discussioncontrasting

confidence: 54%

Section: Levodopa In the Peripherymentioning

confidence: 99%

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

Nord¹

2017

Linköping University Medical Dissertations

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“…Levodopa has a short elimination half-life and stable concentrations are difficult to achieve with oral therapy. Multiple peaks commonly occur in the plasma concentration-time curve for levodopa following oral administration and further exaggerate the variability of plasma concentrations (Evans et al, 1981;Robertson et al, 1989;Wade et al, 1974). It has been suggested that these multiple peaks reflect the manner in which levodopa is delivered from the stomach to the site of carrier-mediated absorption in the small intestine (Evans et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

The influence of levodopa on gastric emptying in man.

Robertson

Renwick

Wood

et al. 1990

Brit J Clinical Pharma

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1. Simultaneous radioisotopic (99Tc‐DTPA) gastric emptying measurements and paracetamol pharmacokinetic studies were performed in eight healthy male volunteers with and without levodopa (125 mg orally). 2. In the absence of levodopa gamma camera imaging showed rapid mono or biexponential emptying in all subjects and the plasma concentration‐ time curves for paracetamol displayed a single major peak. 3. In the presence of levodopa the time to 90% emptying was prolonged from 32 +/‐ 24 min to 81 +/‐ 20 min (P less than 0.01). Gastric emptying was interrupted by a plateau phase in six subjects and this pattern of emptying was associated with double peaks in the plasma concentration‐ time curves of both levodopa and paracetamol. The time to the end of the plateau phase of emptying correlated with the time to the trough plasma concentrations of paracetamol and levodopa. 4. There was excellent agreement between the plasma concentration‐time curves of levodopa and paracetamol, i.e. time to initial peak, r = 0.946, P less than 0.001; time to trough concentration r = 0.943, P less than 0.01; time to second peak r = 0.974, P less than 0.001. 5. The results indicate that levodopa inhibits gastric emptying and thus influences its own absorption. Temporary inhibition of gastric emptying by levodopa (or a metabolite) is the cause of the multiple plasma peaks commonly observed following oral levodopa.

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“…Subsequent samples were withdrawn at the end of the infusion and 5, 10, 15, 30, 45, 60, 75, 90, 105, 120, 180, 240, 300, 360, 420 and 480 min after completion. Plasma was stored at -20°C until analysis as previously described [13].…”

Section: Methodsmentioning

confidence: 99%

The effect of selegiline on the peripheral pharmacokinetics of levodopa in young volunteers.

Waller

O'shea

et al. 1995

Brit J Clinical Pharma

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The plasma pharmacokinetics of levodopa were studied in eight healthy young subjects following an i.v. infusion of 50 mg over 5 min. Subjects were studied on two occasions in random order following treatment with carbidopa; on one occasion they were pretreated with selegiline (four doses of 10 mg over the preceding 3 days) and on the other with a placebo. The mean plasma concentration-time curves on each occasion were essentially superimposable and there were no significant differences in any calculated pharmacokinetic parameter. Selegiline does not significantly alter the distribution or elimination of levodopa from plasma.

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

Cited by 105 publications

References 30 publications

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

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

The influence of levodopa on gastric emptying in man.

The effect of selegiline on the peripheral pharmacokinetics of levodopa in young volunteers.

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