Изворни код странице Farmakokinetika

'''Farmakokinetika''', skraćeno ''PK'', (od [[Старогрчки језик|starogrčkog]] -{''pharmakon''}- "lek" i -{''kinetikos''}- "vezano za kretanje") je grana [[farmakologija|farmakologije]] koja se bavi izučavanjem promena supstanci doziranih u žive organizme. Reč farmakokinetika prvi put uveo je [[Friedrich Hartmut Dost]] 1953. godine u Nemačkoj i disciplinu definisao kao nauku kvantitativne analize odnosa između organizma i leka. Supstance od interesa su farmaceutski agensi, hormoni, nutrijenti, i toksini. Ona pokušava da otkrije sudbinu leka od momenta njegovog unosa do tačke u kojoj je kompletno eliminisan iz tela.
{{Кутијица за цитат
|цитат  = '''Farmakokinetika''' se može jednostavno definisati kao to što telo radi leku, dok je '''farmakodinamika''' usredsređena na to što lek radi telu.<ref>{{Cite book | editor = Horning MG, Mitchell J | title = Drug metabolism and drug toxicity | publisher = Raven Press | location = New York | year = 1984 | isbn = 978-0-89004-997-6 | chapter = Pharmacokinetics: Basic Principles and Its Use as a Tool in Drug Metabolism | chapter-url = http://bts.ucsf.edu/benet_lab/index.php?page=benet | last = Benet | first = LZ | pages =  | access-date = 26. 08. 2013 | archive-date = 20. 10. 2013 | archive-url = https://web.archive.org/web/20131020072723/http://bts.ucsf.edu/benet_lab/index.php?page=benet | url-status = dead }}</ref>
|ширина = 40%
}}
[[Датотека:Gráfica Km.png|мини|250п|Grafikon koji demonstrira [[Михаелис—Ментенина кинетика|Mihaelis-Menteninov kinetički]] model odnosa između enzima i supstrata]]

Farmakokinetika opisuje kako telo deluje na specifični lek nakon doziranja putem mehanizama apsorpcije i distribucije, kao i hemijske promene supstance u telu (e.g. posredstvom metaboličkih enzima kao što su [[enzim]]i [[citohrom P450]] ili [[glukuronoziltransferaza]]), i efekte i puteve izlučivanja metabolita leka.<ref>Pharmacokinetics. (2006). In ''Mosby's Dictionary of Medicine, Nursing, & Health Professions''. Philadelphia, PA: Elsevier Health Sciences. Приступљено December 11, 2008, from http://www.credoreference.com/entry/6686418 </ref> Farmakokinetička svojstva leka mogu da budu uslovljena faktorima poput mesta administriranja i doze leka. Ti faktori mogu da utiču na brzinu apsorpcije.<ref>{{Cite book|author=Kathleen Knights|author2=Bronwen Bryant |title=Pharmacology for Health Professionals |publisher=Elsevier |location=Amsterdam |year=2002 |isbn=978-0-7295-3664-6 |oclc= |doi= |accessdate=|pages=}}</ref> Farmakokinetika se često studira zajedno sa [[farmakodinamika|farmakodinamikom]].

== Pregled ==

Farmakokinetika opisuje kako telo utiče na određeni [[ksenobiotik]]/hemikaliju nakon primene kroz mehanizme apsorpcije i distribucije, kao i na metaboličke promene supstance u telu (npr. metaboličkim [[enzim]]ima kao što su [[citohrom P450]] ili enzimi [[glukuronoziltransferaza|glukuronoziltransferaze]]), i efekte i putevi izlučivanja [[metabolit]]a leka.<ref>Pharmacokinetics. (2006). In ''[[Mosby's Dictionary of Medicine, Nursing & Health Professions]]''. Philadelphia, PA: Elsevier Health Sciences. Retrieved December 11, 2008, from http://www.credoreference.com/entry/6686418</ref> Na farmakokinetička svojstva hemikalija utiču način primene i doza primenjenog leka. Ovo može uticati na stopu apsorpcije.<ref>{{cite book | first1 = Kathleen | last1 = Knights | first2 = Bronwen | last2 = Bryant | title = Pharmacology for Health Professionals | publisher = Elsevier | location = Amsterdam | year = 2002 | isbn = 0-7295-3664-5 }}</ref>

Modeli su razvijeni da pojednostave konceptualizaciju mnogih procesa koji se odvijaju u interakciji između organizma i hemijske supstance. Jedan od njih, [[farmakokinetika#Multi-compartmental models|multipregradni model]], je najčešće korišćena aproksimacija stvarnosti; međutim, složenost koja je uključena u dodavanje parametara sa tim pristupom modelovanju znači da se najčešće koriste ''monokompartmentalni modeli'' i iznad svega ''dvopartmentalni modeli''. Različiti odeljci na koje je model podeljen obično se nazivaju ''ADME'' šema (takođe se nazivaju i LADME ako je oslobađanje uključeno kao poseban korak od apsorpcije):

* [[Liberation (pharmacology)|'''<u>L</u>'''iberacija]] – proces oslobađanja leka iz [[pharmaceutical formulation|farmaceutske formulacije]].<ref name="KochRitschel1986">{{cite book | title = Synopsis der Biopharmazie und Pharmakokinetik | vauthors = Koch HP, Ritschel WA | year = 1986 | publisher = Ecomed | location = Landsberg, München | language = de | isbn = 3-609-64970-4 | chapter = Liberation | pages = 99–131 }}</ref><ref name="pmid17630642">{{cite journal | vauthors = Ruiz-Garcia A, Bermejo M, Moss A, Casabo VG | title = Pharmacokinetics in drug discovery | journal = Journal of Pharmaceutical Sciences | volume = 97 | issue = 2 | pages = 654–90 | date = February 2008 | pmid = 17630642 | doi = 10.1002/jps.21009 }}</ref> Takođe pogledajte [[IVIVC]].
* [[apsorpcija (farmakokinetika)|'''<u>A</u>'''psorpcija]] - proces ulaska supstance u krvotok.
* [[distribucija (farmakologija)|'''<u>D</u>'''istribucija]] – disperzija ili diseminacija supstanci kroz tečnosti i tkiva tela.
* [[метаболизам|'''<u>M</u>'''etabolizam]] (ili biotransformacija, ili inaktivacija) – prepoznavanje od strane organizma da je prisutna strana supstanca i nepovratna transformacija matičnih jedinjenja u metabolite.
* [[систем за излучивање|'''<u>E</u>'''kskrecija]] – uklanjanje supstanci iz tela. U retkim slučajevima, neki [[лек|lekovi]] se nepovratno akumuliraju u [[ткиво (биологија)|tkivu tela]].

== Metrike ==

Sledeće su najčešće merene farmakokinetičke metrike:<ref name="urlwww.agah.info">{{cite web |url = http://www.agah.eu/fileadmin/_migrated/content_uploads/PK-glossary_PK_working_group_2004.pdf |title = Collection of terms, symbols, equations, and explanations of common pharmacokinetic and pharmacodynamic parameters and some statistical functions |author = AGAH working group PHARMACOKINETICS |date = 2004-02-16 |publisher = Arbeitsgemeinschaft für Angewandte Humanpharmakologie (AGAH) (Association for Applied Human Pharmacology) |access-date = 2011-04-04 |archive-url = https://web.archive.org/web/20160508185420/http://www.agah.eu/fileadmin/_migrated/content_uploads/PK-glossary_PK_working_group_2004.pdf |archive-date = 2016-05-08 |url-status = dead }}</ref> Jedinice doze u tabeli su [[мол (јединица)|molske]] (mol) i [[molarna koncentracija|molarne]] (M). Da biste izrazili metriku tabele u jedinicama mase, umesto [[količina supstance]], jednostavno zamenite 'mol' sa 'g' i 'M' sa 'g/dm3'. Slično, druge jedinice u tabeli mogu biti izražene u jedinicama ekvivalentne [[димензија|dimenzije]] skaliranjem.<ref>{{Citation|last1=Hallare|first1=Jericho|title=Half Life|date=2021|url=http://www.ncbi.nlm.nih.gov/books/NBK554498/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=32119385|access-date=2021-12-25|last2=Gerriets|first2=Valerie}}</ref>

{| class="wikitable" style="margin-left: auto; margin-right: auto; border: none;"
|+ Farmakokinetičke metrike
! style="width:6.5em;" | Karakteristika
! Description
! style="width:6em;" | Simbol
! Jedinica
! Formula 
! Vrednost<br />radnog primera
|-
| [[Dose (biochemistry)|Doza]] || Količina primenjenog leka. || <math>D</math>
| <math>\mathrm{mol}</math> || {{n/a|Dizajnirani parameter}}
| 500&nbsp;mmol
|-
| Interval doziranja || Vreme između davanja doze leka. || <math>\tau</math>
| <math>\mathrm{h}</math> || {{n/a|Dizajnirani parameter}}
| 24&nbsp;h
|-
| [[Cmax (farmakologija)|C<sub>max</sub>]] || Maksimalna koncentracija leka u plazmi nakon primene. || <math>C_\text{max}</math>
| <math>\mathrm{mmol/L}</math> || {{n/a|Direktno merenje}}
| 60,9&nbsp;mmol/L
|-
| [[tmax (farmakologija)|t<sub>max</sub>]] || Vreme da se dostigne C<sub>max</sub>. || <math>t_\text{max}</math>
| <math>\mathrm{h}</math> || {{n/a|Direktno merenje}} 
| 3,9&nbsp;h
|-
| [[Cmin (farmakologija)|C<sub>min</sub>]] || Najniža koncentracija koju lek dostigne pre primene sledeće doze.
| <math>C_{\text{min}, \text{ss}}</math>
| <math>\mathrm{mmol/L}</math> || {{n/a|Direktno merenje}}
| 27,7&nbsp;mmol/L
|-
| [[Cavg|C<sub>avg</sub>]] || Prosečna koncentracija leka u plazmi tokom intervala doziranja u [[Steady_state#Pharmacy|stabilnom stanju]].
| <math>C_{\text{av}, \text{ss}}</math>
| <math>\mathrm{h\times mmol/L}</math> || <math>\frac{AUC_{\tau,\text{ss}}}{\tau}</math>
| 55,0&nbsp;h×mmol/L
|-
| [[Volumen distribucije|Zapremina distribucije]] || Prividna zapremina u kojoj se lek distribuira (tj. parametar koji povezuje koncentraciju leka u plazmi sa količinom leka u telu).
| <math>V_\text{d}</math>
| <math>\mathrm{L}</math> || <math>\frac{D}{C_0}</math>
| 6,0&nbsp;L
|-
| [[Концентрација|Koncentracija]] || Količina leka u datoj zapremini [[крвна плазма|plazme]]. || <math>C_{0}, C_\text{ss}</math>
| <math>\mathrm{mmol/L}</math> || <math>\frac{D}{V_\text{d}}</math>
| 83,3&nbsp;mmol/L
|-
| [[Poluvreme eliminacije|Poluvreme apsorpcije]] || Vreme potrebno da se 50% date doze leka apsorbuje u sistemsku cirkulaciju.<ref>[https://www.ncbi.nlm.nih.gov/books/NBK554498/ Half Life]</ref>
| <math>t_{\frac{1}{2}a}</math>
| <math>\mathrm{h}</math> || <math>\frac{\ln(2)}{k_\text{a}}</math>
| 1,0&nbsp;h
|-
| [[Absorption rate constant|Konstanta brzine apsorpcije]] || Brzina kojom lek ulazi u telo oralnim i drugim ekstravaskularnim putevima.
| <math>k_\text{a}</math>
| <math>\mathrm{h}^{-1}</math> || <math>\frac{\ln(2)}{t_{\frac{1}{2}a}}</math>
| 0,693&nbsp;h<sup>−1</sup>
|-
| [[Poluvreme eliminacije|Poluživot eliminacije]] || Vreme potrebno da koncentracija leka dostigne polovinu prvobitne vrednosti.
| <math>t_{\frac{1}{2}b}</math>
| <math>\mathrm{h}</math> || <math>\frac{\ln(2)}{k_\text{e}}</math>
| 12&nbsp;h
|-
| [[Elimination rate constant|Konstanta brzine eliminacije]] || Brzina kojom se lek uklanja iz tela. || <math>k_\text{e}</math>
| <math>\mathrm{h}^{-1}</math> || <math>\frac{\ln(2)}{t_{\frac{1}{2}b}} = \frac{CL}{V_\text{d}}</math>
| 0,0578&nbsp;h<sup>−1</sup>
|-
| [[Stopa infuzije|Brzina infuzije]] || Brzina infuzije potrebna za uravnoteženje eliminacije. || <math>k_\text{in}</math>
| <math>\mathrm{mol/h}</math> || <math>C_\text{ss} \cdot CL</math>
| 50&nbsp;mmol/h
|-
| rowspan=2 | [[Area under the curve (pharmacokinetics)|Površina ispod krive]]
| rowspan=2 | [[Integral]] krive koncentracija-vreme (posle pojedinačne doze ili u stabilnom stanju).
| <math>AUC_{0 - \infty}</math>
| <math>\mathrm{M}\cdot\mathrm{s}</math>
| <math>\int_{0}^{\infty}C\, \mathrm{d}t</math>
| rowspan="2" |1.320&nbsp;h×mmol/L
|-
| <math>AUC_{\tau, \text{ss}}</math>
| <math>\mathrm{M}\cdot\mathrm{s}</math>
| <math>\int_{t}^{t + \tau}C\, \mathrm{d}t</math>
|-
| [[Klirens|Čišćenje]] || Zapremina plazme očišćene od leka u jedinici vremena. || <math>CL</math>
| <math>\mathrm{m}^3/\mathrm{s}</math> || <math>V_\text{d} \cdot k_\text{e} = \frac{D}{AUC}</math>
| 0,38&nbsp;L/h
|-
| [[Биорасположивост|Biološka raspoloživost]] || Sistemski dostupna frakcija leka. || <math>f</math>
| Bezjedinično || <math>\frac{AUC_\text{po} \cdot D_\text{iv}}{AUC_\text{iv} \cdot D_\text{po}}</math>
| 0,8
|-
| [[Peak-to-trough ratio|Fluktuacija]] || Vršna fluktuacija unutar jednog intervala doziranja u stabilnom stanju. || <math>\%PTF</math>
| <math>\%</math>
| <math>100\frac{C_{\text{max}, \text{ss}} - C_{\text{min}, \text{ss}}}{C_{\text{av}, \text{ss}}}</math>
gde je
<math>C_{\text{av}, \text{ss}}=\frac{AUC_{\tau,\text{ss}}}{\tau}</math>
| 41,8%
|}

== Analiza ==

=== Bioanalitičke metode ===

[[Bioanalysis|Bioanalitičke metode]] su neophodne za konstruisanje profila koncentracija-vreme. Za merenje koncentracije lekova u [[biological matrix|biološkoj matrici]], najčešće plazmi, koriste se hemijske tehnike. Odgovarajuće bioanalitičke metode treba da budu selektivne i osetljive. Na primer, [[microscale thermophoresis|mikroskalna termoforeza]] može da se koristi da se kvantifikuje kako biološka matrica/tečnost utiče na afinitet leka za njegovu biološku metu.<ref name=Baaske>{{cite journal | vauthors = Baaske P, Wienken CJ, Reineck P, Duhr S, Braun D | title = Optical thermophoresis for quantifying the buffer dependence of aptamer binding | journal = Angewandte Chemie | volume = 49 | issue = 12 | pages = 2238–41 | date = March 2010 | pmid = 20186894 | doi = 10.1002/anie.200903998}}
*{{cite web |date=February 24, 2010 |title=A hot road to new drugs |website=Phys.org |url=http://www.physorg.com/news186225693.html}}</ref><ref name=Wienken>{{cite journal | vauthors = Wienken CJ, Baaske P, Rothbauer U, Braun D, Duhr S | title = Protein-binding assays in biological liquids using microscale thermophoresis | journal = Nature Communications | volume = 1 | issue = 7 | pages = 100 | date = October 2010 | pmid = 20981028 | doi = 10.1038/ncomms1093 | bibcode = 2010NatCo...1..100W | doi-access = free }}</ref>

=== Masena spektrometrija ===

Farmakokinetika se često proučava korišćenjem [[masena spektrometrija|masene spektrometrije]] zbog složene prirode matriksa (često plazme ili urina) i potrebe za visokom osetljivošću za posmatranje koncentracija nakon niske doze i dugog vremenskog perioda. Najčešća instrumentacija koja se koristi u ovom vidu primene je [[liquid chromatography-mass spectrometry|LC-MS]] sa [[quadrupole mass analyzer|trostrukim kvadrupolnim masenim spektrometrom]]. [[Tandem mass spectrometry|Tandemska masena spektrometrija]] se obično koristi radi dodatne specifičnosti. Standardne krive i interni standardi se koriste za kvantifikaciju obično pojedinačnog leka u uzorcima. Uzorci predstavljaju različite vremenske tačke dok se farmaceutski lek primenjuje, a zatim metaboliše ili uklanja iz tela. Prazni uzorci uzeti pre davanja su važni u određivanju pozadine i obezbeđivanju integriteta podataka sa tako složenim matricama uzoraka. Velika pažnja se poklanja linearnosti standardne krive; međutim, uobičajeno je koristiti [[curve fitting|prilagođavanje krive]] sa složenijim funkcijama kao što su [[квадратна функција|kvadratne]], pošto odziv većine masenih spektrometara nije linearan u velikim opsezima koncentracije.<ref>{{cite journal | vauthors = Hsieh Y, Korfmacher WA | title = Increasing speed and throughput when using HPLC-MS/MS systems for drug metabolism and pharmacokinetic screening | journal = Current Drug Metabolism | volume = 7 | issue = 5 | pages = 479–89 | date = June 2006 | pmid = 16787157 | doi = 10.2174/138920006777697963 | s2cid = 13612670 }}</ref><ref>{{cite journal | vauthors = Covey TR, Lee ED, Henion JD | title = High-speed liquid chromatography/tandem mass spectrometry for the determination of drugs in biological samples | journal = Analytical Chemistry | volume = 58 | issue = 12 | pages = 2453–60 | date = October 1986 | pmid = 3789400 | doi = 10.1021/ac00125a022 }}</ref><ref>{{cite journal | vauthors = Covey TR, Crowther JB, Dewey EA, Henion JD | title = Thermospray liquid chromatography/mass spectrometry determination of drugs and their metabolites in biological fluids | journal = Analytical Chemistry | volume = 57 | issue = 2 | pages = 474–81 | date = February 1985 | pmid = 3977076 | doi = 10.1021/ac50001a036 }}</ref>

Trenutno postoji značajno interesovanje za korišćenje masene spektrometrije veoma visoke osetljivosti za studije [[microdosing|mikrodoziranja]], koje se vide kao obećavajuća alternativa [[animal experimentation|eksperimentisanju na životinjama]].<ref name="EMEA-MD">{{cite web |url=http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002720.pdf |title=ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals |author=Committee for Medicinal Products for Human Use (CHMP) |date=December 2009 |id=EMA/CPMP/ICH/286/1995 |publisher=[[Evropska agencija za lekove|European Medicines Agency]], Evaluation of Medicines for Human Use |access-date=4 May 2013 |archive-date=15. 06. 2018 |archive-url=https://web.archive.org/web/20180615083052/http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002720.pdf |url-status= }}</ref> Nedavne studije pokazuju da se [[Secondary electrospray ionization|sekundarna elektrosprejna jonizacija]] (SESI-MS) može koristiti u praćenju lekova, što pruža prednost izbegavanja žrtvovanja životinja.<ref>{{Cite journal|last1=Li|first1=Xue|last2=Martinez-Lozano Sinues|first2=Pablo|last3=Dallmann|first3=Robert|last4=Bregy|first4=Lukas|last5=Hollmén|first5=Maija|last6=Proulx|first6=Steven|last7=Brown|first7=Steven A.|last8=Detmar|first8=Michael|last9=Kohler|first9=Malcolm|last10=Zenobi|first10=Renato|date=2015-06-26|title=Drug Pharmacokinetics Determined by Real-Time Analysis of Mouse Breath|journal=Angewandte Chemie International Edition|language=en|volume=54|issue=27|pages=7815–7818|doi=10.1002/anie.201503312|pmid=26015026|hdl=20.500.11850/102558|hdl-access=free}}</ref>

== Vidi još ==
* [[Bioraspoloživost]]
* [[Enzimska kinetika]]
* [[Farmakodinamika]]

== Reference ==
{{reflist|}}

== Literatura ==
{{Литература|30em}}
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* {{Cite book|author=Kathleen Knights|author2= Bronwen Bryant |oclc= |doi= |location=Amsterdam|publisher=Elsevier|year=2002|isbn=978-0-7295-3664-6|pages= |title=Pharmacology for Health Professionals }}
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* {{cite journal|date= 2006|title= Increasing speed and throughput when using HPLC-MS/MS systems for drug metabolism and pharmacokinetic screening|journal=Current Drug Metabolism |volume=7|issue=5|pages=479–89|doi= 10.2174/138920006777697963|pmid= 16787157|last1= Hsieh|first1= Y.|last2= Korfmacher|first2= W. A.|s2cid= 13612670}}
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{{Литература крај}}

== Spoljašnje veze ==
* https://web.archive.org/web/20070304050519/http://vam.anest.ufl.edu/demos/onecompbolus.html
* http://cti.itc.virginia.edu/~cmg/Demo/scriptFrame.html {{Wayback|url=http://cti.itc.virginia.edu/~cmg/Demo/scriptFrame.html |date=20070308150244 }}
* https://web.archive.org/web/20150924105610/http://www.staff.uni-giessen.de/~gi38/publica/pharma/pharma.pdf

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