drug permeation through intestine

39
DRUG PERMEATION THROUGH INTESTINE Mario Grassi Department of Chemical Engineering (DICAMP) UINVERSITY OF TRIESTE

Upload: reeves

Post on 25-Feb-2016

44 views

Category:

Documents


0 download

DESCRIPTION

DRUG PERMEATION THROUGH INTESTINE. Mario Grassi Department of Chemical Engineering (DICAMP) UINVERSITY OF TRIESTE. Farmaco. BIODISPONIBILITA’ “Frazione della dose di principio attivo che diviene disponibile al sito (fisiologico) di azione dopo somministrazione”. INTRODUCTION. - PowerPoint PPT Presentation

TRANSCRIPT

Page 1: DRUG PERMEATION THROUGH INTESTINE

DRUG PERMEATION THROUGH INTESTINE

Mario Grassi

Department of Chemical Engineering (DICAMP)UINVERSITY OF TRIESTE

Page 2: DRUG PERMEATION THROUGH INTESTINE

BIODISPONIBILITA’

“Frazione della dose di principio attivo che diviene disponibile al sito (fisiologico) di azione dopo somministrazione”

Farmaco

Page 3: DRUG PERMEATION THROUGH INTESTINE

INTRODUCTIONWHICH IS OUR PROBLEM?

Delivery system

Page 4: DRUG PERMEATION THROUGH INTESTINE

TWO ASPECTS MUST BE CONSIDERED

DRUG RELEASE FROM THE DELIVERY SYSTEM

DRUG ABSORPTION AND

METABOLISM/EXCRETION

Page 5: DRUG PERMEATION THROUGH INTESTINE

SETTING UP OUR PROBLEM

Modern Biopharmaceutics, version 6.03, G. L. Amidon, M. Bermejo, TSRL inc, produced by Judy C. Price.

Page 6: DRUG PERMEATION THROUGH INTESTINE

Modern Biopharmaceutics, version 6.03, G. L. Amidon, M. Bermejo, TSRL inc, produced by Judy C. Price.

Page 7: DRUG PERMEATION THROUGH INTESTINE

DOSAGEFORM

DRUGSOLUTION

SYSTEMIC CIRCULATION

(BLOOD)

GASTROINTESTINALTRACT

CELLULARMEMBRANE

DISSOLUTIONLIMITED

PERMEABILITYLIMITED

0 – CENTRAL POINT: ADME

BLOOD and DEEPER COMPARTMENT

ABSORPTION

DISTRIBUTION

METABOLISM

EXCRETION

Page 8: DRUG PERMEATION THROUGH INTESTINE

Pharmacokinetics is the study of the time course of drug absorption, distribution, metabolism and excretion (ADME), and how these ADME processes are related to the intensity and time course of the pharmacological (therapeutic and toxic) effects of drugs

1 – PHARMACOKINETICS

Page 9: DRUG PERMEATION THROUGH INTESTINE

METABOLISM - EXCRETION

LiverFirst pass metabolism

Delivery System

Pre-systemic metabolsim

Gutmetabolism

Systemic metabolsim

Heart

lung

Kidney

Excretion

Excretion

Modern Biopharmaceutics, version 6.03, G. L. Amidon, M. Bermejo, TSRL inc, produced by Judy C. Price.

Page 10: DRUG PERMEATION THROUGH INTESTINE

F = Fa * Fg * Fh *Fl = BIOAVAILABILITY

SYSTEMIC CIRCULATION

Page 11: DRUG PERMEATION THROUGH INTESTINE

CLEARANCE

“Is the volume of blood that must be cleared of drug per unit time in order to account for drug elimination”

Blood flow

Continuous Drug Supply

Q Drug elimination

Cd

Page 12: DRUG PERMEATION THROUGH INTESTINE

Blood flow

FILTER

Clearing Blood flow

Cd

Q1

Qc

Q

TOTAL DRUG ELIMINATION

NO DRUG ELIMINATION

Qc= CLEARANCE

Page 13: DRUG PERMEATION THROUGH INTESTINE

INTRA VINUS CLEARANCE: Cliv

Cliv= DOSE/AUC

C(mass/volume)

T (time)

AUC

Page 14: DRUG PERMEATION THROUGH INTESTINE

Blood concentration

0

50

100

150

200

250

300

350

0 5 10 15 20 25

t (h)

C(n

g/m

l)

Cls = Dose/ AUC

Cls = 100 / 0.001 = 104 ml/s

ORAL CLEARANCE: Cloral

Page 15: DRUG PERMEATION THROUGH INTESTINE

Cloral = Cliv/ (Fa*Fg*Fh* Fl)F = bioavailability

Page 16: DRUG PERMEATION THROUGH INTESTINE

DISTRIBUTION VOLUME: V

“Is a measure of the extent of drug distribution and is determined by the drug binding in plasma as well as tissues.”

V = Vb + Vt fb/ft

Vb = blood volumeVt = tissues volume

fb = drug unbound fraction in bloodft = drug unbound fraction in tissues

Page 17: DRUG PERMEATION THROUGH INTESTINE

ELIMINATION HALF TIME: T1/2

T1/2 = 0.693 V/Cls

Page 18: DRUG PERMEATION THROUGH INTESTINE

2 – SMALL INTESTINE STRUCTURE

The small intestine is the longest section of the digestive tube and consists of three segments forming a passage from the pylorus to the large intestine

Duodenum:a short section that receives secretions from the pancreas and liver via the pancreatic and common bile ducts

Jejunum: considered to be roughly 40% of the small gut in man, but closer to 90% in animals.

empties into the large intestine; considered to be about 60% of the intestine in man, but veterinary anatomists usually refer to it as being only the short terminal section of the small intestine.

Ileum:

Page 19: DRUG PERMEATION THROUGH INTESTINE

Small intestine is suspended from the body wall by an extension of the peritoneum called the mesentery.

Lymphatic vessels are also present, but are not easy to discern grossly in normal specimens.

blood vessels to and from the intestine lie between the two sheets of the mesentery.

Page 20: DRUG PERMEATION THROUGH INTESTINE

T. Serosa: In most of the digestive tract (stomach and intestines) it consists of a thin layer of loose connective tissue covered by mesothelium (a type of squamous epithelium that lines body cavities)

T. Muscularis: endows the digestive tube with an ability to be motile.

Page 21: DRUG PERMEATION THROUGH INTESTINE

T. Submucosa: immediately beneath the mucosa, is a layer of loose to dense connective tissue containing blood and lymphatic vesselsT. Mucosa: Among the four tunics, the mucosa is most variable in structure and function, endowing the tube with an ability to perform diverse and specialized digestive tasks along its length. Of critical importance are the epithelial cells that cover the mucosa and are thus in direct contact with the lumen.

Page 22: DRUG PERMEATION THROUGH INTESTINE

Substances absorption and much of the enzymatic digestion takes place on the surface of small intestinal epithelial cells, and to accomodate these processes, a huge mucosal surface area is required.

Lumenal surface area ≈ 0.5 m2

Real absorptive surface area ≈ 250 m2

Small Intestine macroscopic folding

Page 23: DRUG PERMEATION THROUGH INTESTINE

Height = 0.5 - 1 mmDiameter = 0.1 mm

Height = 1 mDiameter = 0.1 m

Page 24: DRUG PERMEATION THROUGH INTESTINE

SCHEMATIC REPRESENTATION OF VILLI

Page 25: DRUG PERMEATION THROUGH INTESTINE

pH = 4.0 – 5.5

DUODENUM

STOMACH: pH = 1.2 - 2pH

= 5

.5 –

7

JEJUNUM

pH = 5.5 – 7

ILEUM

S. I. Lumen

STAGNANT LAYER(300 m) pH = 0.5 LAYER

(≈ 20 m)

pH VARIATIONS

AHHAka

HLogpH 10

Page 26: DRUG PERMEATION THROUGH INTESTINE

3 – CELLS MEMBRANE STRUCTURE

CELLS MEMBRANE: FLUID MOSAIC MODEL

The double layer results from the orientation of the amphiprotic lipids (phospholipids, glycolipids, cholesterol) in the aqueous medium

Page 27: DRUG PERMEATION THROUGH INTESTINE

In the membrane, different proteins are embedded performing different functions. Some proteins form selective ion-channels (Na+, K+, Ca++, Cl-).

Page 28: DRUG PERMEATION THROUGH INTESTINE

By the interaction of membrane proteins at the contact surfaces between single cells so called tight junctions are formed. In most

membranes, these tight junctions contain fenestrae, which can be regarded as pores filled with water

Page 29: DRUG PERMEATION THROUGH INTESTINE

TIGHT JUNCTIONS

PARACELLULAR

4 – ABSORPTION MECHANISMS

PASSIVE: DIFFUSION DUE TO CHEMICAL POTENTIAL GRADIENT

TRANCELLULAR

+

-BASOLATERAL

APICAL

CATIONS

ANIONS

Page 30: DRUG PERMEATION THROUGH INTESTINE

In the small intestine, the surface area presented by paracellular route constitutes only a small fraction (0.01%) of the total membrane surface area

DRUG MW < 200

TRANSCELLULARIMPORTANT

PARACELLULAR IMPORTANT

DRUG MW > 200

TRANSCELLULARIMPORTANT

PARACELLULAR NOT IMPORTANT

Page 31: DRUG PERMEATION THROUGH INTESTINE

FACILITATED DIFFUSION

MEMBRANE PROTEINS (CARRIER C)

BIND TO DIFFUSANT

(AA AMINOACIDS; SUGAR S)

IMPROVING ITS DIFFUSION ACROSS

CELL MEMBRANE.

FdAA and FdS INDICATE AA AND S

CONCENTRATION GRADIENT

Page 32: DRUG PERMEATION THROUGH INTESTINE

FILTRATION

All passive diffusion processes my be

superimposed by an osmotic water flow,

able to drag along the molecules (=

solvent drug)

Page 33: DRUG PERMEATION THROUGH INTESTINE

ACTIVE: ENERGY IS SUPPLIED TO DIFFUSANT

Endocytosis or Transcytosis:Very large molecules are transported by invagination of the membrane and subsequent vesiculation and devesiculation

Co-transport:Target molecule associates to another compound that crosses the cellular membrane due to the existing concentration gradient (this the case of glucose and aminoacids that associate to Na+ crossing the cellular membrane according to the concentration gradient).

ATP pump:Energy required for molecules transport is supplied by the hydrolysis of high energy compounds such as ATP (ATP => ADP + P + energy). A typical example is represented by the Na+ - K+ pump.

Page 34: DRUG PERMEATION THROUGH INTESTINE

0 6 12 18 24

t(h)

Con

cent

razi

one

(g/

ml) limite di tossicità

limite terapeutico

t(h)

Con

cent

razi

one

(mg/

ml) limite di tossicità

limite terapeutico

sistema tradizionale

sistema a ril. contr.

4 – CONTROLLED RELEASE SYSTEMS

Page 35: DRUG PERMEATION THROUGH INTESTINE

SRCSISTEMA A RILASCIO CONTROLLATO

AUMENTO DELLA PERFORMANCE(EFFICACIA TERAPEUTICA, COSTI)

PROGETTAZIONE

MODELLI MATEMATICI

MODELLI MATEMATICI

MODELLI MATEMATICI

MODELLI MATEMATICI

Page 36: DRUG PERMEATION THROUGH INTESTINE

CRS CATEGORIES

1 PASSIVE PREPROGRAMMED

2 ACTIVE PREPROGRAMMED

2 ACTIVE SELF PREPROGRAMMED

Page 37: DRUG PERMEATION THROUGH INTESTINE

Chamber ISWELLABLE GEL

Chamber IIAQUEOUS SOLUTION

Chamber IIIINSULIN SOLUTION

Glucose permeable membrane(diffusion)

Inward oneway valve(convection)

Outward oneway valve(convection)

Rigid housing

diaphgram

partition

Chamber ISWELLABLE GEL

Chamber IIAQUEOUS SOLUTION

Chamber IIIINSULIN SOLUTION

Glucose permeable membrane(diffusion)

Inward oneway valve(convection)

Outward oneway valve(convection)

Rigid housing

diaphgram

partition

Page 38: DRUG PERMEATION THROUGH INTESTINE

MEMBRANE IMMUNOISOLANTI

RILASCIO DI INSULINA

L. Leoni et al., Advanced Drug Delivery Review, 56 (2004) 211

INSULINMICROFABRICATED

MEMBRANE55

8 m

ENCAPSULATED CELLS

IMMUNOGLOBULINS Na+, K+, Oxygen, Glucose

Page 39: DRUG PERMEATION THROUGH INTESTINE

S. Z. Razzacki et al., Advanced Drug Delivery Review, 56 (2004) 185