Drug in dosage form Release Drug particles in body fluids Dissolution Drug in solution Degradation Pharmacologic effect

Peripheral Tissues Distribution Central Compartment Free ' Bound

GIAbsorption Liver Excretion

Movement of Drugs in the BodySite of Action

Absorption

Drug in Blood

Metabolism

Toxicity

Tissues Bound Drug in Blood

Excretion

Pharmacokinetics

PharmacokineticsOr: Does the drug actually reach its site of action? This is governed by three factors: 1. Absorption: Uptake of the drug from the compartment of application into the blood 2. Distribution: Transport / equilibration between the blood and the rest of the organism 3. Elimination: Filtration and secretion in the kidneys; chemical modification in the liver

Determine the time needed to reach the target

Determines the time available

Mekanisme : Absorpsi (tahap awal); penembusan zat aktif (efek farmakologi); saat mencapai target mel.perantaraan darah perubahan hayati (metabolisme) eliminasi Penyerapan; penetrasi Berbeda utk Distribusi/metabolisme; difusisetiap bahan aktif

Kesamaan

perlintasan melalui membran biologis

MEMBRAN BIOLOGIS

Definisihalangan/sawar yang dilalui zat aktif sebelum mengalami proses ADME

Bentuk - susunan beberapa lapisan sel ; kulit- satu sel basal; epitel sel usus halus - ukuran lebih kecil dari sel; membran antar sel

merupakan satu kesatuan struktur yang sama utk semua membran (hewan, manusia, tumbuhan)

Sifat MembranKonsep : - Overton lapisan tipis, bahan menyerupai lemak - Stain and Danielli terdapat pori diantara 2 lap.lemak - Singer & Nicholson (Mozaik cair) lap.ganda muskolipid yg tdk sinambung yang salah satu sisi nya disisipi protein - Pratt & Taylor membran tdd 2 pori (diameter 10 nm dan 50-70 nm); air, ion dan zat terlarut dpt melintasi membran

polar

non polar

protein

Struktur Mosaik (konsep Singer&Nicholson)

Molekul lipoid

protein

pori

Konsep Steinn dan Danielli

PASSAGE OF XENOBIOTICS ACROSS BIOLOGICAL MEMBRANES

PHYSICOCHEMICAL DETERMINANTS OF THE PASSAGE OF XENOBIOTICS ACROSS BIOLOGICAL MEMBRANES

A. Membrane Characteristics1. Membrane CompositionMembrane Type General Inner mitochondrial Myelin Phospholipid 40% 20-25% 75% Protein 60% 75-80% 25%

phospholipid{ non-polar tail polar head

A. Membrane Characteristics2. Membrane Structure

Fluid-mosaic model of Singer and Nicholson (Science 175:720-731, 1972

Membrane Composition Structure of Lipid Bilayers

Membrane Structure

Terdiri atas : 2 basal lipid monomolekular fosfolipid dan kolesterol Kutub hidrofob ke bagian dalam Kutub hidrofil pada bagian luar

Struktur Membran Sel (lanjutan)Tebal 75 A 2 kutub hidrofil mengandung protein dan ujung fosfolipid yang polar susunan statis Model dinamik yang banyak diterima : Mosaik Cair Matrik membran terdiri dari 2 lapisan lipid protein globular yang tidak berkesinambungan dan saling menyesuaikan Gugus polar terletak pada permukaan membran dan non polar di dalam Tebal pori 85 A A

Membran selbarrier of drug permeation, with semipermeable property factor affecting drug across cell membrane A.cell membrane properties A.cell B. physicochemical properties of drugssize and shape solubility degree of ionization lipid solubility

A.Characteristics of Cell membrane A.Characteristics Lipid bilayer: mobile horizontally, flexible, high electrical resistance and impermeable to high polar compounds protein molecules function as receptors or ion channels or sites of drug actions.

B. Drug Characteristics molecular weight, shape, sizeTissue jejunem ileum Estimated Pore Radius 7.5 A 3.5Aunstirred layer

cell

lipid solubility ionization

solubility in unstirred layer around cell

MECHANISMS OF BIOTRANSPORTBiotransportThe translocation of a solute from one side of a biological barrier to the other side in the intact form.

Passive DiffusionExternal Internal

semi-permeable membrane

Movement of Drug MoleculesThis process is called passive diffusion No cellular effort is needed to transport the molecules (hence the process is passive)

Drug molecules move randomly from one point to another

Passive DiffusionMovement is random from areas of higher to areas of lower concentration Eventually the drug molecules are equally distributed (equilibrium)

High concentration in this area

Passive DiffusionC e l l M e m b r a n e But drug molecules will only cross by passive diffusion if they can dissolve in the membrane

Drug molecules may move from one side of a cell membrane to another by passive diffusion

Difusi PasifTranspor dari kadar tinggi ke rendah Gaya pendorong : gradien konsentrasi V = P (Ce - Ci) V = D A K (Ce - Ci) (X Laju difusi tergantung pada : Tetapan difusi obat dalam bahan lipoid (D) Luas permukaan membran (A) Koefisien partisi (K) Tebal membran ((X) (( Gradien konsentrasi

The most common transport process for absorption of chemical compounds in passive diffusion. Depends upon diffusion through phospholipid bilayer Must be a [ ] gradient across membrane Compound must be lipid soluble Compound must be in non-ionized state non-

Structuresimple cylinder Folds of Kerckring

Increase in Surface (relative to cylinder) 1 3

Surface Area sq cm 3,300 10,000

Villi

30

100,000

Microvilli

600

2,000,000

Transpor Aktif Arah absorpsi dari konsentrasi rendah ke tinggi Diperlukan carrier dan energi Carrier merupakan konstituen membran, enzym yang mampu membentuk komplek dengan zat aktif dipermukaan membran selanjutnya memindahkannya dan dilepaskan ke sisi lain, lalu carrier kembali ke tempat semula

Active TransportC e l l M e m b r a n e The drug molecule encounters the carrier molecule The cell expends energy to PUMP the molecule across the membrane to the other side

Involves a carrier molecule again

Active TransportC e l l M e m b r a n e The drug molecule encounters the carrier molecule The cell expends energy to PUMP the molecule across the membrane to the other side

Involves a carrier molecule again

Active TransportC e l l M e m b r a n e Unlike diffusion, active transport is not dependent upon concentration gradient All of the molecules can end up on this side

Involves a carrier molecule again

Transpor Dipermudah (fasilitatif) Mekanisme seperti transpor aktif tapi tidak butuh energi Contoh : sianokobalamin yang membentuk komplek dengan faktor intrinsik yang dihasilkan dinding lambung.

Facilitated DiffusionC e l l M e m b r a n e These drug molecules need a carrier to get across the membrane

These molecules cant pass through the membrane without help

Facilitated DiffusionC e l l M e m b r a n e When the drug molecule encounters the carrier protein, it carries it across

Here is the carrier protein molecule in the membrane

Facilitated DiffusionC e l l M e m b r a n e When the drug molecule encounters the carrier protein, it carries it across

Here is the carrier protein molecule in the membrane

Facilitated DiffusionC e l l M e m b r a n e When the drug molecule encounters the carrier protein, it carries it across

Here is the carrier protein molecule in the membrane

Facilitated DiffusionC e l l M e m b r a n e The carrier molecule then resets itself No cellular energy is used to transport the molecule across Only the concentration gradient moves the molecules

Here is the carrier protein molecule in the membrane

Active and Facilitated Transport: a specific membrane carrier system is required the process may be saturated at high substrate concentrations substrates may compete for uptake5-fluorouracil, an anticancer drug, is absorbed by the pyrimidine transport system Lead is absorbed by the calcium transport system

CHARACTERISTICS OF CARRIERCARRIERMEDIATED TRANSPORTFacilitated Diffusion Movement against a concentration gradient Utilization of energy Exhibits saturation Example substances Active Transport

no no yes riboflavin, Vit B12

yes yes yes 5-flurouracil

Membrane Transporters and Their SubstratesTransporterAmino acid transporters

Substratesbaclofen, cyclosporin, L-dopa, baclofen, cyclosporin, Lgabapentin, gabapentin, methyldopa F-lactam antibiotics, ACE inhibitors, cephalexin, cyclosporin, methyldopa cephalexin, cyclosporin, zidovudine, zalcitabine, dipyridamole zidovudine, zalcitabine,

Peptide transporters (hPEPT1, HPT1) Nucleoside transporters (CNT1, CNT2) Organic anion transporters (OATP1, OATP3, OATP8)

ceftriaxone, benzoic acid, methotrexate ceftriaxone, pravastatin

Organic cation transporters thiamine, desipramine, quinidine, desipramine, quinidine, (OCT1,OCT2) midazolam, verapamil midazolam, Bile acid transporters (IBAT/ISBT) chlorambucil, thyroxine chlorambucil,

Pinositosis Proses memungkinkan absorpsi molekul-molekul besar melewati membran dikarenakan kemampuan membran membalut bahan obat dengan membentuk sejenis vesikule (badan dibalut) yang menembus membran Contoh : Absorpsi Vit A, D, E, K

Phagocytosis and PinocytosisForeign particle

Cell

Phagocytosis the cell flows around large particles and engulfs it

Pinocytosis cell takes in molecules through invations in the membrane

Transpor pasangan ion Transpor senyawa-senyawa terionisasi sangat kuat pada pH fisiologis Contoh : senyawa amonium kuarterner dan asam-asam sulfonat Pembentukan kompleks netral (pasangan ion) dengan substansi endogen seperti mucin memungkinkan difusi pasif dengan melewati membran

Filtrasi / konvektif Melalui pori membran (secara pasif) yang disebabkan gradien tekanan hidrostatik atau osmotik Transpor obat BM kecil (< 150) larut dalam air Laju absorpsi dipengaruhi oleh laju absorpsi air, ukuran molekul dan ukuran pori