Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics

Kompoliti, Katie; Adler, Charles H.; Raman, Rema; Pincus, Jonathan H.; Leibowitz, Mark; Ferry, James J.; Blasucci, Lucy M.; Caviness, John N.; Leurgans, Sue E.; Chase, W. M.; Yones, L. C.; Tan, Ern Yu; Carvey, Paul M.; Goetz, Christopher G.

doi:10.1212/wnl.58.9.1418

Cited by 65 publications

(45 citation statements)

References 13 publications

(14 reference statements)

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“…Because the changes in RNA levels precede the changes at the protein level, as shown for PEPT1 (Qandeel et al, 2009), we may have missed RNA changes that potentially took place earlier. Differences in the circadian cycle of male and females as observed in our study are not yet well understood (Bailey and Silver, 2014), but importantly, gender differences have also been suggested to play a major role in PD patients (Kompoliti et al, 2002;Steffansen et al, 2004;Miller and Cronin-Golomb, 2010;Pavon et al, 2010;Doi et al, 2012).…”

Section: Discussionmentioning

confidence: 52%

“…Absorption of levodopa in humans follows a circadian rhythm with faster absorption during day and delayed absorption during night (Nyholm et al, 2010). Furthermore, gender differences in levodopa bioavailability and in clinical presentation were observed (Kompoliti et al, 2002;Martinelli et al, 2003). We analyzed the expression of transporters involved in levodopa transport in the small intestine of male and female rodents during the active (related to daytime in humans) and nonactive phase (related to night-time in humans).…”

Section: Levodopa Transport In Intestinementioning

confidence: 99%

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The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

Camargo

Vuille‐dit‐Bille

Mariotta

et al. 2014

J Pharmacol Exp Ther

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Levodopa (L-DOPA) is the naturally occurring precursor amino acid for dopamine and the main therapeutic agent for neurologic disorders due to dopamine depletion, such as Parkinson's disease. L-DOPA absorption in small intestine has been suggested to be mediated by the large neutral amino acids transport machinery, but the identity of the involved transporters is unknown. Clinically, coadministration of L-DOPA and dietary amino acids is avoided to decrease competition for transport in intestine and at the bloodbrain barrier. L-DOPA is routinely coadministered with levodopa metabolism inhibitors (dopa-decarboxylase and cathechol-O-methyl transferase inhibitors) that share structural similarity with levodopa. In this systematic study involving Xenopus laevis oocytes and Madin-Darby canine kidney epithelia expression systems and ex vivo preparations from wild-type and knockout mice, we identified the neutral and dibasic amino acids exchanger (antiporter) AT-rBAT substrates, whereas dopadecarboxylase and cathechol-O-methyl transferase inhibitors had no effect. The presence of amino acids in the basolateral compartment mimicking the postprandial phase increased transepithelial levodopa transport by stimulating basolateral efflux via the antiporter LAT2-4F2 (SLC7A8-SLC3A2). Additionally, the aromatic amino acid uniporter TAT1 (SLC16A10) was shown to play a major role in L-DOPA efflux from intestinal enterocytes. These results identify the molecular mechanisms mediating small intestinal levodopa absorption and suggest strategies for optimization of delivery and absorption of this important prodrug.

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Section: Discussionmentioning

confidence: 52%

Section: Levodopa Transport In Intestinementioning

confidence: 99%

The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

Camargo

Vuille‐dit‐Bille

Mariotta

et al. 2014

J Pharmacol Exp Ther

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“…Other studies have also found a sex difference in bioavailability of the dopaminergic agonist, pramipexole, which is often used in conjunction with levodopa to potentiate the dopaminergic effect. In these studies, females were demonstrated to have a 24-27% lower oral clearance for pramipexole as compared to males [128]. This further suggests there is a sex difference in the clearance of dopaminergic agents that may play a role in sex-specific dosing of PD medications.…”

Section: Parkinson's Diseasementioning

confidence: 85%

Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications

et al. 2007

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Estrogen is an important hormone signal that regulates multiple tissues and functions in the body. This review focuses on the neurotrophic and neuroprotective actions of estrogen in the brain, with particular emphasis on estrogen actions in the hippocampus, cerebral cortex and striatum. Sex differences in the risk, onset and severity of neurodegenerative disease such as Alzheimer's disease, Parkinson's disease and stroke are well known, and the potential role of estrogen as a neuroprotective factor is discussed in this context. The review assimilates a complex literature that spans research in humans, non-human primates and rodent animal models and attempts to contrast and compare the findings across species where possible. Current controversies regarding the WHI (Women's Health Initiative) study, its ramifications, concerns and the new studies needed to address these concerns are also addressed. Signaling mechanisms underlying estrogen-induced neuroprotection and synaptic plasticity are reviewed, including the important concepts of genomic versus nongenomic mechanisms, types of estrogen receptor involved and their subcellular targeting, and implicated downstream signaling pathways and mediators. Finally, a multicellular mode of estrogen action in the regulation of neuronal survival and neurotrophism is discussed, as are potential future directions for the field.

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“…Orally administrated levodopa in human is mainly decarboxylated in the GI tract (45) and in brain capillary endothelium (46) but also in liver and kidney. It has been shown that the bioavailability of levodopa is higher in women compared to men (47,48) and oestrogen is not the responsible factor (47). It is more likely the result of differences in COMT activity between gender (48).…”

Section: Levodopa In the Peripherymentioning

confidence: 99%

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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Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics

Cited by 65 publications

References 13 publications

The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications

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

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