Effect of transporter inhibition on the distribution of cefadroxil in rat brain

Chen, Xiaomei; Loryan, Irena; Payan, Maryam; Keep, Richard F.; Smith, David Eugene; Hammarlund‐Udenaes, Margareta

doi:10.1186/2045-8118-11-25

Cited by 24 publications

(16 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Depending on the tissue studied, it is difficult to influence the probe length. When measuring CSF concentrations in cisterna magna in rats, only a 1-mm probe length is possible (55), while a 3-mm probe length can be used in striatum, and a 10-mm probe length in vena jugularis (56).…”

Section: Flow Rates and Probe Lengthsmentioning

confidence: 99%

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Hammarlund‐Udenaes

2017

AAPS J

Self Cite

View full text Add to dashboard Cite

Abstract.Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions. Quantitative microdialysis developed very rapidly during the early 1990s. Method development was in focus in the early years including development of quantitative microdialysis, to be able to estimate true extracellular concentrations. Microdialysis has significantly contributed to the understanding of active transport at the blood-brain barrier and in other organs. Examples are presented where microdialysis together with modeling has increased the knowledge on tissue distribution between species, in overweight patients and in tumors, and in metabolite contribution to drug effects. More integrated metabolomic studies are still sparse within the microdialysis field, although a great potential for tissue and disease-specific measurements is evident.

show abstract

Section: Flow Rates and Probe Lengthsmentioning

confidence: 99%

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Hammarlund‐Udenaes

2017

AAPS J

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cefadroxil is a substrate of several CNS barrier transporters including the organic anion transporters (OATs) [29], multidrug resistance-associated proteins (MRPs) [30,31], and organic anion transporting polypeptides (OATPs) [32]. Moreover, our previous study showed that co-administration of probenecid (an inhibitor of OATs, MRPs, and OATPs) caused a 2.5-fold increase in the K p,uu of cefadroxil in rat brain ECF during microdialysis [22]. This finding supports our current study results, suggesting that cefadroxil is, indeed, effluxed from brain to plasma by PEPT2 along with the OATs, MRPs and/or OATPs.…”

Section: Discussionmentioning

confidence: 99%

“…At present, cephalosporin antibiotics (e.g., ceftriaxone and cefotaxime) used to treat CNS infections [48] are not PEPT2 substrates [49]. Cefadroxil, as a substrate of multiple efflux transporters including PEPT2, has very low levels in CSF and brain ECF, thereby, excluding its use for CNS infections [22]. Thus, caution should be exercised in developing drug candidates having the general structural features of PEPT2 substrates [3,50] for diseases of the brain.…”

Section: Discussionmentioning

confidence: 99%

“…Microdialysis also has the advantage of enabling repeated sampling without fluid loss on freely moving animals. In our previous microdialysis study in rats [22], an attempt was made to investigate the role of PEPT2 on cefadroxil disposition in ECF and CSF by functional ablation of PEPT2 via competitive inhibition of cefadroxil transport using intraventricular infusion of the dipeptide Ala-Ala. Unfortunately, the results were negative, probably because of the biological instability of Ala-Ala in vivo [23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study

Chen

Keep

Liang

et al. 2017

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

Peptide transporter 2 (PEPT2) is a high-affinity low-capacity transporter belonging to the proton-coupled oligopeptide transporter family. Although many aspects of PEPT2 structure-function are known, including its localization in choroid plexus and neurons, its regional activity in brain, especially extracellular fluid (ECF), is uncertain. In this study, the pharmacokinetics and regional brain distribution of cefadroxil, a β-lactam antibiotic and PEPT2 substrate, were investigated in wildtype and Pept2 null mice using in vivo intracerebral microdialysis. Cefadroxil was infused intravenously over 4 hours at 0.15 mg/min/kg, and samples obtained from plasma, brain ECF, cerebrospinal fluid (CSF) and brain tissue. A permeability-surface area experiment was also performed in which 0.15 mg/min/kg cefadroxil was infused intravenously for 10 min, and samples obtained from plasma and brain tissues. Our results showed that PEPT2 ablation significantly increased the brain ECF and CSF levels of cefadroxil (2- to 2.5-fold). In contrast, there were no significant differences between wildtype and Pept2 null mice in the amount of cefadroxil in brain cells. The unbound volume of distribution of cefadroxil in brain was 60% lower in Pept2 null mice indicating an uptake function for PEPT2 in brain cells. Finally, PEPT2 did not affect the influx clearance of cefadroxil, thereby, ruling out differences between the two genotypes in drug entry across the blood-brain barriers. These findings demonstrate, for the first time, the impact of PEPT2 on brain ECF as well as the known role of PEPT2 in removing peptide-like drugs, such as cefadroxil, from the CSF to blood.

show abstract

“…A Margareta Hammarlund-Udenaes vezette svéd kutatócsoport agyi mikrodialízissel vizsgálta mind az agyszöveti ECF, mind pedig az oldalkamrai liquor (CSF) cefadroxilkoncentrációit probenecid -mint OAT, OATP és MRP inhibitor -jelenlétében és hiányában [35] patkányokon. Nagaya és mtsai majmokon végzett kísérlete-ikben hasonlították össze a mikrodializátumokban, illetve a ciszternális liquorban mérhető anyagkoncentrációkat P-gp szubsztrátok esetén [36].…”

Section: Vizsgálati Módszerekunclassified

Gyógyszertranszporterek szerepe a központi idegrendszerben

Temesszentandrási-Ambrus

Beéry

2016

Orvosi Hetilap

View full text Add to dashboard Cite

Bár a vér-agy gát jelenlétét az emlősszervezetekben már a XX. század elején felismerték, pontos szerkezetét, illetve a benne található gyógyszertranszporter fehérjéket csak az utóbbi évtizedekben azonosították. A központi idegrendszer védelmét biztosító ATP-kötő kazettatranszporter pumpafehérjék mellett fontos szerepet játszanak az idegrendszer működésében a solute carrier transzporterek is, amelyek a táplálék-és energiaellátást biztosítják, illetve a metabolizmus során "eltakarító" funkciót is betöltenek. Az összefoglaló közlemény áttekintést ad az idegrendszerben előforduló főbb transzporter fehérjetípusokról, sejttípusonkénti lokalizációjukról, illetve a vizsgálatukra szolgáló főbb módszerekről. A közlemény második felében különböző neurodegeneratív betegségek és a patológiájukkal összefüg-gésbe hozható transzporter fehérjék kerülnek bemutatásra. Mindezek fényében olyan új terápiás stratégiák kerülhet-nek a figyelem középpontjába, amelyek a jelenleg gyógyíthatatlan betegségek esetében jelenthetnek majd megoldást. Orv. Hetil., 2016, 157(10), 370-378. Kulcsszavak: membrántranszporterek, vér-agy gát, neurodegeneratív betegségek, központi idegrendszer Role of drug transporters in the central nervous systemAlthough the presence of blood-brain barrier in the mammalian organisms was discovered in the early 1900s, its precise structure and the drug transporter proteins localized in the blood-brain barrier were identified only in the last decades. Beside the ATP-binding cassette transporter proteins responsible for the protection of the brain, the Solute Carrier transporters play also an important role in the function of the central nervous system by its feeding, energy supply and cleaning function during the metabolism. This review provides an overview on the main types of transporters located in the brain, on their localization in different cell types and the main techniques for their investigation. In the second part of this article various neurodegenerative disorders and the pathology-related transporter proteins are presented. In the light of recent experimental results new therapeutic strategies may come into the focus of research for the treatment of disorders currently without effective therapy. Rövidítések Aβ = béta-amiloid protein; ABC = ATP-binding cassette transporter; AIDS = acquired immunodeficiency syndrome; ALS = amyotrophiás lateralsclerosis; ANLSH = astrocyta-neuron laktát sönt hipotézis; ATP = adenozin-trifoszfát; BCRP = breast cancer resistance protein; Caco2 = caucasian colon adenocarcinoma cell line; CSF = cerebrospinal fluid; CTL = kolintranszporter; DAT = dopamintranszporter; EAAT = excitáns aminosav-transzporter; ECF = extracellular fluid; FDA = Food and Drug Administration; GABA = gamma-aminovajsav; GAT = GABA-transzporter; GLAST = glutamát-aszpartát transzporter; GLT = glutamáttranszporter; GLUT = glükóztranszpor-ter; GlyT = glicintranszporter; hCMEC/D3 = human cerebral microvascular endothelial cell line; HIV = human immunodeficiency virus; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; K...

show abstract

Effect of transporter inhibition on the distribution of cefadroxil in rat brain

Cited by 24 publications

References 48 publications

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study

Gyógyszertranszporterek szerepe a központi idegrendszerben

Contact Info

Product

Resources

About