Osnove farmakokinetike
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1 Osnove farmakokinetike prof. dr. Lovro Stanovnik Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
2 Farmakologija Vedo o delovanju zdravilih in drugih snovi v telesu. Farmakodinamika učinkovanje zdravila na telo Farmakokinetika delovanje telesa na zdravilo
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4 Osnovna farmakokinetska dogajanja (ADME) Absorpcija zdravila z mesta aplikacije Porazdelitev po telesu (distribucija) Metabolizem (biotransformacija) Izločanje iz organizma (ekskrecija, eliminacija) Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
5 Faktorja, ki vplivata na koncentracijo zdravila na mestu delovanja Organizem sestavljen iz več predelkov (kompartmentov) enakomerna porazdelitev zdravila enaka koncentracija oprehajanje molekul zdravila med kompartmenti oprehod na mesto delovanja. Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
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7 Bariere med kompartmenti Med znotrajcelično in zunajcelično tekočino celična membrana Epitelne bariere (črevo, ledvice) dve celični membrani Endotel žil razlike med organi Bariera med krvjo in možgani endotel žil drugačen druge celice (periciti, celice glije) Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
8 Prehajanje zdravil v organizmu Prenašanje s topilom (pretok krvi) pomembno pri časovnem poteku razporeditve zdravil. Difuzija (posamezne molekule, kratke razdalje) pomembna pri prehajanju zdravil preko ovir (barier), ki ločujejo telesne kompartmente Prenašanje s transportnimi sistemi (prenašalci) Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
9 Prehajanje zdravil preko celičnih membran Direktna difuzija skozi plasti lipidov. Difuzija skozi vodne pore posebni transmembranski proteini ('akvaporini ). Vezava na transmembranski prenašalni protein sprememba konformacije sprostitev na drugi strani membrane. Pinocitoza. Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
10 Figure 7-1 Routes by which solutes can traverse cell membranes. (Molecules can also cross cellular barriers by pinocytosis.) Downloaded from: StudentConsult (on 26 February :43 PM) 2005 Elsevier
11 Prehajanje zdravil preko lipidnih membran Topnost v lipidih Narava zdravila (šibke baze ali kisline) Stopnja disociacije odvisna od kislosti (ph) okolja (opisuje jo vrednost pk a ) Nedisociirana molekula bolj topna v lipidih Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
12 Figure 7-2 The importance of lipid solubility in membrane permeation. Figure shows the concentration profile in a lipid membrane separating two aqueous compartments. A lipid-soluble drug (A) is subject to a much larger transmembrane concentration gradient (ΔCm) than a lipid-insoluble drug (B). It therefore diffuses more rapidly, even though the aqueous concentration gradient (C1-C2) is the same in both cases. Downloaded from: StudentConsult (on 26 February :43 PM) 2005 Elsevier
13 Figure 7-3 Theoretical partition of a weak acid (aspirin) and a weak base (pethidine) between aqueous compartments (urine, plasma and gastric juice) according to the ph difference between them. Numbers represent relative concentrations (total plasma concentration = 100). It is assumed that the uncharged species in each case can permeate the cellular barrier separating the compartments, and therefore reaches the same concentration in all three. Variations in the fractional ionisation as a function of ph give rise to the large total concentration differences with respect to plasma. IONIC TRAPPING Downloaded from: StudentConsult (on 26 February :43 PM) 2005 Elsevier
14 Figure 7-4 pka values for some acidic and basic drugs. Downloaded from: StudentConsult (on 26 February :43 PM) 2005 Elsevier
15 Osnovna farmakokinetska dogajanja (ADME) Absorpcija zdravila z mesta aplikacije Porazdelitev po telesu (distribucija) Metabolizem (biotransformacija) Izločanje iz organizma (ekskrecija, eliminacija) Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
16 Absorpcija zdravil Mesta aplikacije Peroralna Sublingvalna Rektalna Aplikacija na druge epitelne površine (koža, kornea, vagina in nazalna mukoza) Inhalacija Injekcija (parenteralna aplikacija): Subkutana Intramuskularna Intravenska Intratekalna. Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
17 Značilnosti posameznih delov prebavil Usta venska kri mimo jeter hitra pasaža Želodec nizek ph (1 3), možnost razpada zdravila (ph, encimi), hitra pasaža Duodenum, jejunum, ileum ph med 6 in 7, velika absorptivna površina (villi), glavno mesto enteralne absorpcije zdravil Rektum venska kri mimo portalnega obtoka Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
18 Figure 7-7 Absorption of drugs from the intestine, as a function of pka, for acids and bases. Weak acids and bases are well absorbed; strong acids and bases are poorly absorbed. (Redrawn from Schanker L S et al J Pharmacol 120: 528.) Downloaded from: StudentConsult (on 2 March :48 PM) 2005 Elsevier
19 Biološka uporabnost zdravil (bioavailability, F) Delež zdr., ki pride iz prebavil v sistemsko cirkulacijo 40 Konc. zdravila v plazmi AUC konc. i.v. konc. p.o Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
20 Koncentracija Površina pod krivuljo - AUC Čas Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
21 Biološka uporabnost zdravila Faktor absorpcije zdravila F = AUC AUC po.. iv.. Biološko uporabnost omejuje: Nepopolna absorpcija z mesta aplikacije (večinoma peroralna) Metabolizem v črevesni steni oz. v jetrih pred prihodom v sistemsko cirkulacijo (metabolizem prvega prehoda) Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
22 Drugi načini aplikacije zdravil APLIKACIJA NA EPITELNE POVRŠINE Kutana aplikacija Nazalni sprayi Očesne kapljice Inhalacija ADMINISTRACIJA Z INJICIRANJEM Metode za zakasnitev absorpcije Intratekalno injiciranje Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
23 Inhalacija respiratorni sistem Učinkovito absorbtivno področje Sistemsko delovanje (inhalacijski anestetiki) Lokalno delovanje: na gladko muskulaturo bronhijev na konsistenco bronhialne sluzi pomembna velikost delcev mesto odlaganja možnost sistemskih učinkov.
24 Vpliv na porazdelitev zdravil Vezava na plazemske beljakovine Porazdelitev v maščevju in drugih tkivih Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
25 Figure 7-9 The main body fluid compartments, expressed as a percentage of body weight. Drug molecules exist in bound or free form in each compartment, but only the free drug is able to move between the compartments. Downloaded from: StudentConsult (on 26 February :44 PM)
26 Odvisnost volumnov posameznih kompartmentov starost: stari volumen tekočin, novorojenček volumen spol (m > f) fiziološka stanja: (nosečnost vode v telesu, debelost vode)
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28 Volumen porazdelitve Volumen, v katerem bi se enakomerno porazdelilo zdravilo, če bi imelo povsod tako koncentracijo, kot jo ima v plazmi Navidezen volumen V D = Q C pl Q količina zdravila v telesu C pl koncentracija v plazmi
29 V D je odvisen od: pk a zdravila Porazdelitvenega koeficienta Vezave na plazemske beljakovine posebno pomembna, če V D < 10 L (0,15 L/kg) (interakcije!) Razlike v regionalnem pretoku krvi Vezave v tkivih
30 Biotransformacija zdravil Živali kompleksni sistemi za odstranjevanje telesu tujih snovi (ksenobiotiki) strupene rastline Zdravila poseben primer ksenobiotikov Distribucija lipofilne snovi kopičenje v tkivih Hidrofilne snovi se laže in hitreje izločajo. Biotransformacija zdravil 2 fazi: I in II (običajno si sledita). Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
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32 Rezultati biotransformacije Nastanek neaktivnega metabolita (nepolarna snov polarna snov) Iz zdravila nastane aktiven metabolit primeri: Neaktivna oblika (predzdravilo) Aktivno zdravilo Aktivni metabolit Azathioprine Merkaptopurin Kortizon Hidrokortizon Prednizon Prednizolon Enalapril Enalaprilat Zidovudin Zidovudin trisfosfat Toksični metabolit Ciklofosfamid Fosforamidni derivat akrolein Diazepam Morfin Nordiazepam Morfine 6-glukuronid Oxazepam Halotan Trifluoroocetna k. Paracetamol N-Acetil-pbenzokvinonimin
33 Fazi biotransformacije Reakcije I faze so katabolne (npr. oksidacija, redukcija ali hidroliza) produkti često kemično bolj reaktivni (lahko tudi bolj toksični) Reakcije II faze so sintetske (anabolne) konjugacija manj aktivni produkti (praviloma). I faza poveča reaktivnost molekule priprava na konjugacijo. Obe fazi povečata hidrofilnost molekule. Mesta biotransformacije jetra (gladki ER mikrosomi), GIT (MAO), plazma (holinesteraza), pljuča Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
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35 The fraction of clinically used drugs metabolized by the major phase 1 and phase 2 enzymes. The relative size of each pie section represents the estimated percentage of drugs metabolized by the major phase 1 (panel A) and phase 2 (panel B) enzymes, based on studies in the literature. In some cases, more than a single enzyme is responsible for metabolism of a single drug. CYP, cytochrome P450; DPYD, dihydropyrimidine dehydrogenase; GST, glutathione-s-transferase; NAT, N-acetyltransferase; SULT, sulfotransferase, TPMT, thiopurine methyltransferase; UGT, UDP-glucuronosyltransferase.
36 Faktorji, ki vplivajo na metabolizem zdravil Inhibicija metabolnih encimov (nekatera zdravila, sok grenivke sprememba učinkov antihipertenzivov, imunosupresivov, antidepresivov, antihistaminikov, statinov. Naringin in furanokumarini inhib. CYP3A4). Genski polimorfizem individualne razlike (NAT) Indukcija encimov (CYP): Avtoindukcija Heteroindukcija Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
37 Metabolizem 1. prehoda Intenzivna razgradnja ob prvem prehodu skozi jetra Manjša biološka uporabnost zdravila Manjše koncentracije zdravila v plazmi Primeri: Aspirin Gliceril trinitrat Izosorbid dinitrat Levodopa Lidokain Metoprolol Morfin Propranolol Salbutamol Verapamil
38 Poti eliminacije zdravil Ledvice urin: predvsem hidrofilne snovi Jetra žolč (hepatobiliarni sistem) Pljuča izdihan zrak: lahko hlapne snovi (splošni anestetiki) Druge poti: mleko slina znoj Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
39 Izločanje skozi ledvice Večina zdravil prehaja glomerulni filter (nevezani del). Šibke kisline in šibke baze aktivna sekrecija v proksimalnem tubulu hitrejša ekskrecija. Liposolubilna zdravila pasivna reabsorpcija z difuzijo preko stene tubula slaba eliminacija. Porazdelitev odvisna od ph šibke kisline: hitrejše izločanje v alkalnem urinu in vice versa. Številna zdravila: eliminacija v glavnem z renalno ekskrecijo toksičnost pri starejših, pri prizadetosti ledvic. Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
40 Examples of drugs that are excreted largely unchanged in the urine Percentage Drugs excreted Furosemide (frusemide), gentamicin, methotrexate, atenolol, digoxin Benzylpenicillin, cimetidine, oxytetracycline, neostigmine ~50 Propantheline, tubocurarine Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
41 Important drugs and related substances actively secreted into the proximal renal tubule Acids p-aminohippuric acid Furosemide (frusemide) Glucuronic acid conjugates Glycine conjugates Indometacin Methotrexate Penicillin Sulfate conjugates Thiazide diuretics Uric acid Bases Amiloride Dopamine Histamine Mepacrine Morphine Pethidine Quaternary ammonium probenecid compounds Quinine 5-Hydroxytryptamine (serotonin) Triamterene Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani
42 Renalni klirens (izčistek) zdravila, Cl Cl = hitrost ekstrakcije c pl Cl ren C Q = u u C pl Q: pretok Enote: ml/min Inulin: ~ 120 ml/min Kreatinin: ~ 125 ml/min Pri odraslem mera za GFR Novorojenčki: hitrost glomerulne filtracije je zmanjšana!
43 Hitrosti farmakokinetskih procesov Kinetika prvega reda (linearna kinetika): hitrost upadanja koncentracije zdravila v plazmi premo sorazmerna s koncentracijo Kinetika ničelnega reda: hitrost upadanja neodvisna od koncentracije
44 Figure 10.3 Predicted behaviour of single-compartment model following intravenous drug administration at time 0. Drugs a and b differ only in their elimination rate constant, kel. Curve b' shows the plasma concentration time course for a smaller dose of b. Note that the half-life (t1/2) (indicated by broken lines) does not depend on the dose. [A] Linear concentration scale. [B] Logarithmic concentration scale. Downloaded from: StudentConsult (on 28 July :22 AM) 2005 Elsevier
45 t 1/2 Čas, v katerem pade koncentracija zdravila v plazmi na polovico. Navadno traja 3 5 t 1/2, da pade količina zdravila pod mejo, ki lahko povzroča učinke
46 Figure 10.5 The effect of slow drug absorption on plasma drug concentration. [A] Predicted behaviour of singlecompartment model with drug absorbed at different rates from the gut or an injection site. The elimination halftime is 6 h. The absorption half-times (t1/2 abs) are marked on the diagram. (Zero indicates instantaneous absorption, corresponding to intravenous administration.) Note that the peak plasma concentration is reduced and delayed by slow absorption, and the duration of action is somewhat increased. [B] Measurements of plasma aminophylline concentration in humans following equal oral and intravenous doses. (Data from Swintowsky J V 1956 J Am Pharm Assoc 49: 395.) Downloaded from: StudentConsult (on 28 July :22 AM) 2005 Elsevier
47 Figure 10.9 Comparison of non-saturating and saturating kinetics for drugs given orally every 12 h. [A] The curves showing an imaginary drug, similar to the antiepileptic drug phenytoin at the lowest dose, but with linear kinetics. The steady-state plasma concentration is reached within a few days, and is directly proportional to dose. [B] Curves for saturating kinetics calculated from the known pharmacokinetic parameters of phenytoin (see Ch. 44). Note that no steady state is reached with higher doses of phenytoin, and that a small increment in dose results after a time in a disproportionately large effect on plasma concentration. (Curves were calculated with the Sympak pharmacokinetic modelling program written by Dr J G Blackman, University of Otago.) Downloaded from: StudentConsult (on 28 July :22 AM) 2005 Elsevier
48 Farmakokinetika etanola Absorpcija: dobra, predvsem iz tankega črevesja, max. 30 min po zaužitju (prazen želodec) Distribucija: v telesne tekočine (0,5 0,7 L/g) (odvisna od hitrosti pitja, vnosa hrane, spola, telesne mase, količine vode v telesu ) Metabolizem: individualno pogojen, intenziven metabolizem prvega prehoda (odvisen od spola aktivnost ADH v želodcu). Aspirin inhibira ADH v želodcu. Upadanje koncentracije v plazmi kinetika 0. reda Izločanje: 2-10% nespremenjen z urinom, izdihanim zrakom (2000:1), znojem
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