The search for tacrine derivatives, as potential Alzheimer´s disease treatment, is still being at the forefront of scientific efforts. 7-MEOTA was found to be a potent, centrally active acetylcholinesterase inhibitor free of the serious side effects observed for tacrine. Unfortunately, a relevant argumentation about pharmacokinetics and potential toxicity is incomplete; information about tacrine derivatives absorption and especially CNS penetration are still rare as well as detailed toxicological profile in vivo. Although the structural changes between these compounds are not so distinctive, differences in plasma profile and CNS targeting were found. The maximum plasma concentration were attained at 18th min (tacrine; 38.20 ± 3.91 ng/ml and 7-MEOTA; 88.22 ± 15.19 ng/ml) after i.m. application in rats. Although the brain profiles seem to be similar; tacrine achieved 19.34 ± 0.71 ng/ml in 27 min and 7-MEOTA 15.80 ± 1.13 ng/ml in 22 min; the tacrine Kp (AUCbrain/AUCplasma) fit 1.20 and was significantly higher than 7-MEOTA Kp 0.10. Administration of tacrine and 7-MEOTA showed only mild elevation of some biochemical markers following single p.o. application in 24 hours and 7 days. Also histopathology revealed only mild-to-moderate changes following repeated p.o. administration for 14 days. It seems that small change in tacrine molecule leads to lower ability to penetrate through the biological barriers. The explanation that lower p.o. acute toxicity of 7-MEOTA depends only on differences in metabolic pathways may be now revised to newly described differences in pharmacokinetic and toxicological profiles.

• MeSH
• časové faktory MeSH
• cholinesterasové inhibitory aplikace a dávkování   farmakokinetika   toxicita   MeSH
• krysa rodu rattus MeSH
• mozek metabolismus   MeSH
• plocha pod křivkou MeSH
• potkani Wistar MeSH
• takrin aplikace a dávkování   analogy a deriváty   farmakokinetika   toxicita   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Being among the top five causes of death in the developed world, Alzheimer's disease represents a major socio-economic issue. We administered a single intramuscular dose of two new hybrid anti-Alzheimer's compounds, with 7-methoxytacrine (7-MEOTA; acetylcholinesterase inhibitor) and tryptophan (inhibitor of amyloid accumulation) in their structure, to rats. Using validated ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) methods, we uncovered their inability to enter the site of action - the brain. We discuss four possible explanations: i) physico-chemical properties, ii) lack of active/facilitated transport, iii) effective efflux and/or iv) extensive metabolism. High-resolution mass spectrometric analyses proved that the compounds are easily hydrolysed at amide bond between tryptophan and the linker both in vitro and in vivo. Contrary to the parent compounds these metabolites - analogues of 7-MEOTA - can enter the brain in significant amounts.

• MeSH
• Alzheimerova nemoc MeSH
• cholinesterasové inhibitory farmakokinetika   MeSH
• hematoencefalická bariéra MeSH
• hydrolýza MeSH
• krysa rodu rattus MeSH
• mozek metabolismus   MeSH
• potkani Wistar MeSH
• takrin analogy a deriváty   farmakokinetika   MeSH
• tandemová hmotnostní spektrometrie MeSH
• tryptofan farmakokinetika   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non-selective AChE/BChE 7-MEOTA-donepezil-like inhibitors for potential therapeutic use in Alzheimer's disease (AD) patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently, the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC-37 and eight metabolites of PC-48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principal metabolic pathways in vitro. Of these metabolites, M1-M7 of PC-37 and M1-M6 of PC-48 were confirmed under in vivo conditions. Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavailability expressed as AUCtotal was 28179 ± 4691 min.ng/mL for PC-37 and 23374 ± 4045 min.ng/mL for PC-48. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile). All these characteristics are crucial for new candidates intended for AD treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites, but this needs to be confirmed by further studies.

• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• biologická dostupnost MeSH
• cholinesterasové inhibitory chemická syntéza   metabolismus   farmakokinetika   terapeutické užití   MeSH
• hydrolýza MeSH
• hydroxylace MeSH
• jaterní mikrozomy metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• mozek účinky léků   MeSH
• pilotní projekty MeSH
• piperaziny chemická syntéza   metabolismus   farmakokinetika   terapeutické užití   MeSH
• potkani Wistar MeSH
• takrin analogy a deriváty   chemická syntéza   metabolismus   farmakokinetika   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

A simple, rapid and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated for the quantitative determination in rat plasma of a new candidate for AD treatment, namely PC 48 (a 7-MEOTA-donepezil like compound) in rat plasma. Sample preparation involved pH adjustment with sodium hydroxide followed by solvent extraction with ethyl acetate:dichloromethane (80:20, v/v). The chromatographic separation was achieved on an Ascentis Express RP-Amide column (75 mm × 2.1mm, 2.7 μm) with a gradient mobile phase consisting of 0.05 M aqueous formic acid and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry on an LTQ XL system using the MS/MS CID (collision-induced dissociation) mode. The method was linear in the range 0.1-1000 ng/ml (r(2)=0.999) with a lower limit of quantitation of 0.1 ng/mL. Extraction recovery was in the range 63.5-72.1% for PC 48 and 70.5% for reserpine (internal standard, IS). Intra- and inter-day precisions measured as relative standard deviation were below 10.8% and accuracy was from -7.2% to 7.4%. The method was successfully applied to a pharmacokinetic study involving intramuscular application of 3.86 mg/kg PC 48 to rats for the first time. Pharmacokinetic parameters for PC 48 include Cmax 39.09 ± 4.45 ng/mL,Tmax 5.00 ± 3.08 min, AUC0-t 23374 ± 4045 min ng/mL and t1/2 1065 ± 246 min.

• MeSH
• Alzheimerova nemoc MeSH
• cholinesterasové inhibitory krev   MeSH
• indany krev   chemie   farmakokinetika   MeSH
• krysa rodu rattus MeSH
• lineární modely MeSH
• piperidiny krev   chemie   farmakokinetika   MeSH
• potkani Wistar MeSH
• reprodukovatelnost výsledků MeSH
• senzitivita a specificita MeSH
• takrin analogy a deriváty   krev   chemie   farmakokinetika   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• antidota aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• arsenikové přípravky škodlivé účinky   MeSH
• atropin aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• chemická válka prevence a kontrola   MeSH
• chemické bojové látky klasifikace   škodlivé účinky   MeSH
• chemický terorismus prevence a kontrola   MeSH
• cholinesterasy aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• financování organizované MeSH
• fysostigmin aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• karbamáty aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• lidé MeSH
• obidoxim chlorid aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• organofosfáty škodlivé účinky   toxicita   MeSH
• propanoly aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• sarin škodlivé účinky   toxicita   MeSH
• takrin aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• trihexyfenidyl aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• trimedoxim aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• yperit škodlivé účinky   toxicita   MeSH
• Check Tag
• lidé MeSH

• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• lidé MeSH
• takrin aplikace a dávkování   farmakokinetika   farmakologie   MeSH
• Check Tag
• lidé MeSH

7-Methoxytacrine (7-MEOTA) is an acetylcholine-esterase inhibitor that is potentially useful in the therapy of some neurodegenerative disorders. L-carnitine (CRT) is a naturally occuring compound that is known to increase penetration of some compounds through biological barriers. Aim of this study was how CRT influenced transintestinal absorption transport 7-MEOTA in rat using single-pass intestinal in situ perfusion method. The rate of absorption of 7-MEOTA during luminal perfusion with single 7-MEOTA was compared with rate of absorption during simultaneous perfusion with 7-MEOTA and CRT and with absorption rate after the premedication with CRT for period of three days before beginning of perfusion. The methodical system was the perfusion of mesenterial bed (from arteria mesenterica superior to vena portae) and intestinal luminal perfusion (from duodenum to ileum). The lower transintestinal absorption in the course of simultaneously administration of CRT than just in case of perfusion with single 7-MEOTA has been found. On the contrary a significantly higher absorption of 7-MEOTA has been noted in group of rats premedicated with CRT for three consecutive days. The interpretation suggested that molecules of CRT incorporated into the metabolism of intestinal cells facilitated transport of 7-MEOTA (as a representative substance which is at least partly transferred by carrier mechanism). In case of simultaneous luminal perfusion with CRT and 7-MEOTA competitive over-saturation of carrier systems is probably.

• MeSH
• cholinesterasové inhibitory farmakokinetika   MeSH
• intestinální absorpce účinky léků   MeSH
• karnitin farmakologie   MeSH
• krysa rodu rattus MeSH
• perfuze metody   MeSH
• potkani Wistar MeSH
• takrin analogy a deriváty   farmakokinetika   MeSH
• vitamin B komplex farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Experimental determinantion of anticholinesterase ctivity,principal pharmacokinetics,and hepatotoxicity of the cognitive drugs 7-methoxytacrine and galanthamine. Testing of their interaction with L-carnitine,acetyl L.carnitine,cyclosporine A and nimodopine with the aim to contribute to the higher effectiveness of therapeutic approaches in cognitive disorders.

Experimentální sledování anticholinesterázové aktivity,základní farmakokinetiky a hepatotoxicity kognitiv 7-methoxytacrinu a galanthaminu. Testování jejich interakce s L-karitinem,acetyl-L-karnitinem,cyklosporinem A a nimodipinem s cílem přispět k vyššíefektivitě terapeutických přístupů u kognitivních poruch.

• MeSH
• cyklosporin analogy a deriváty   aplikace a dávkování   farmakokinetika   MeSH
• karnitin analogy a deriváty   aplikace a dávkování   farmakokinetika   MeSH
• modely u zvířat MeSH
• nootropní látky aplikace a dávkování   farmakokinetika   MeSH
• takrin analogy a deriváty   aplikace a dávkování   farmakokinetika   MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• farmacie a farmakologie
• neurologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

• MeSH
• acetylcholinesterasa antagonisté a inhibitory   fyziologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• farmakokinetika účinky léků   MeSH
• finanční podpora výzkumu jako téma MeSH
• hematoencefalická bariéra MeSH
• karnitin farmakologie   MeSH
• krysa rodu rattus MeSH
• takrin analogy a deriváty   farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

• Klíčová slova
• HUPERAZIN, METRIFONAT,
• MeSH
• acetylcholinesterasa antagonisté a inhibitory   farmakokinetika   farmakologie   MeSH
• donepezil MeSH
• galantamin MeSH
• rivastigmin MeSH
• takrin farmakokinetika   farmakologie   škodlivé účinky   MeSH
• Publikační typ
• přehledy MeSH