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Absorption, distribution, metabolism and excretion PowerPoint PPT Presentation


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Absorption, distribution, metabolism and excretion. relevant to ALL drugs large research/development area frequent cause of failure of treatment failure of compliance failure to achieve effective level produce toxic effects can enhance patient satisfaction with treatment.

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Absorption, distribution, metabolism and excretion

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Absorption distribution metabolism and excretion l.jpg

Absorption, distribution, metabolism and excretion

  • relevant to ALL drugs

  • large research/development area

  • frequent cause of failure of treatment

    • failure of compliance

    • failure to achieve effective level

    • produce toxic effects

  • can enhance patient satisfaction with treatment


Learning objectives l.jpg

Learning objectives

  • Know the processes involved in ADME of drugs

  • Know how these processes may affect the action of xenobiotics

  • Appreciate how these processes can affect the outcome of the treatment of patients with drugs

  • Appreciate how differences in these processes between patients can affect therapy

  • Know how these processes have been exploited to improve therapy

  • Be able to exemplify the above


Passage through lipid membranes l.jpg

Passage through lipid membranes

  • diffusion through gaps between cells (glomerulus = 68K; capillary 30K)

  • passage through the cell membrane

    • diffuse through pore (very small; use dependent)

    • carrier mediated transport (specific, saturable; Fe in gut; L-DOPA at blood-brain barrier; anion/cation transport in kidney)

    • pinocytosis (insulin in CNS; botulinum toxin in gut)

    • diffusion through lipid of cell membrane (depends on AREA, DIFFUSION GRADIENT, DIFFUSION COEFFICIENT, LIPID SOLUBILITY)


Weak acids and weak bases l.jpg

Weak acids and weak bases

HA <==> H+ + A- B + HCl <==> BH+ + Cl-

[ UI ] [ I ] [ UI ] [ I ]

pKa=pH+log(HA/A-) pKa=pH+log(BH+/B)

pKa = 4.5 (a weak acid)

pH = 2

pH = 7.4

0.1 = [ I ]

[ I ] = 9990

100 = [ UI ]

[ UI ] = 100

100.1 = total drug = 10090


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Routes of administration

  • Enteral;oral, sub-lingual (buccal), rectal

  • Parenteral;iv, im, sc, id, it, etc.

  • Surface; of skin, of lungs? for local or systemic effect?

  • Inhalation; local or systemic effect?

  • Vaginal;(usually local)

  • Eye; (usually local)


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Factors affecting oral absorption

  • Disintegration of dosage form

  • Dissolution of particles

  • Chemical stability of drug

  • Stability of drug to enzymes

  • Motility and mixing in GI tract

  • Presence and type of food

  • Passage across GI tract wall

  • Blood flow to GI tract

  • Gastric emptying time


Bioavailability l.jpg

Bioavailability

  • the proportion of the drug in a dosage form available to the body

    i.v injection gives 100% bioavailability.

    Calculated from comparison of the area under the curve (AUC) relating plasma concentration to time for iv dosage compared with other route.

    Says nothing about effectiveness.


Bioavailability8 l.jpg

Bioavailability

Destroyed

in gut

Not

absorbed

Destroyed

by gut wall

Destroyed

by liver

Dose

to

systemic

circulation


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Sustained release preparations

  • depot injections (oily, viscous, particle size)

  • multilayer tablets (enteric coated)

  • sustained release capsules (resins)

  • infusors(with or without sensors)

  • skin patches (nicotine, GTN)

  • pro-drugs

  • liposomes

    Targeted drugs , antibody-directed


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Distribution into body compartments

  • Plasma 3.5 litres, heparin, plasma expanders

  • Extracellular fluid 14 litres, tubocurarine, charged polar compounds

  • Total body water 40 litres, ethanol

  • Transcellular small, CSF, eye, foetus (must pass tight junctions)

    Plasma protein binding; Tissue sequestration


Alter plasma binding of drugs l.jpg

Alter plasma binding of drugs

1000 molecules

90.0

99.9

% bound

1

100

molecules free

100-fold increase in free pharmacologically

active concentration at site of action.

EffectiveTOXIC


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Biotransformation of drugs

  • Mutations allowing de-toxification of natural toxic materials are advantageous and are selected

  • Drugs are caught up in these established de-toxification processes

  • Drugs may converted to

    less toxic/effective materials

    more toxic/effective materials

    materials with different type of effect or toxicity


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Sites of biotransformation

  • where ever appropriate enzymes occur; plasma, kidney, lung, gut wall and

    LIVER

  • the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation


The liver l.jpg

The liver

Hepatocytes

smooth

endoplasmic

reticulum

bile

portal

venous

blood

microsomes

contain cytochrome P450

dependent

mixed function oxidases

systemic

arterial

blood

venous blood


Cytochrome p450 dependent mixed function oxidases l.jpg

Cytochrome P450 dependent mixed function oxidases

DRUG

METABOLITE

=DRUG+O

O2

microsome

NADP+

NADPH

WATER

H+


Slide16 l.jpg

PHASE 1 reactions

Hydroxylation -CH2CH3 -CH2CH2OH

Oxidation -CH2OH -CHO -COOH

O-de-alkylation -CH2OCH2- -CH2OH

+ -CHO

N-de-alkylation -N(CH3)2 -NHCH3

+ CH3OH

N-oxidation -NH2 -NHOH

Oxidative deamination -CH2CHCH3

|

-CHCOCH3 + NH3 NH2


Phase i in action l.jpg

Phase I in action

4-OH;

active;

cardiotoxic

4-OH;

active;

cardiotoxic

0

0

N

CH2

CH2

N

CH3 CH3

desmethyl;

active;

antidepressant

+Conjugates;

phase II


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PHASE 2 reactions(not all in liver)

CONJUGATIONS

  • -OH, -SH, -COOH, -CONH with glucuronic acid to give glucuronides

  • -OH with sulphate to give sulphates

  • -NH2, -CONH2, aminoacids,sulpha drugs with acetyl- to give acetylated derivatives

  • -halo, -nitrate, epoxide, sulphate with glutathione to give glutathione conjugates

    all tend to be less lipid soluble and therefore better excreted (less well reabsorbed)


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Other (non-microsomal) reactions

  • Hydrolysis in plasma by esterases (suxamethonium by cholinesterase)

  • Alcohol and aldehyde dehydrogenase in cytosolic fraction of liver (ethanol)

  • Monoamine oxidase in mitochondria (tyramine, noradrenaline, dopamine, amines)

  • Xanthene oxidase (6-mercaptopurine, uric acid production)

  • enzymes for particular drugs (tyrosine hydroxylase, dopa-decarboxylase etc)


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Inhibitors and inducers of microsomal enzymes

  • INHIBITORS cimetidine

    prolongs action of drugs or inhibits action of those biotransformed to active agents (pro-drugs)

  • INDUCERS barbiturates, carbamazepineshorten action of drugs or increase effects of those biotransformed to active agents

  • BLOCKERS acting on non-microsomal enzymes (MAOI, anticholinesterase drugs)


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Factors affecting biotransformation

  • age (reduced in aged patients & children)

  • sex (women more sensitive to ethanol?)

  • species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); route of biotransformation can also change

  • race (fast and slow isoniazid acetylators, fast = 95% Eskino; 50% Brits; 13% Finns; 13% Egyptians.

  • clinical or physiological condition

  • first-pass (pre-systemic) metabolism


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Excretion of drugs

  • Glomerular filtration allows drugs <25K MW to pass into urine; reduced by plasma protein binding; only a portion of plasma is filtered.

  • Tubular secretion active carrier process for cations and for anions; inhibited by probenicid.

  • Passive re-absorption of lipid soluble drugs back into the body across the tubule cells.

    Note effect of pH to make more of weak acid drug present in ionised form in alkaline pH therefore re-absorbed less and excreted faster; vica-versa for weak bases.


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Special aspects of excretion

  • lactating women in milk

  • little excreted in faeces unless poor formulation or diarrhoea

  • volatile agents (general anaesthetics) via lungs

  • the entero-hepatic shunt glucuronic acid conjugates with MW >300 are increasingly excreted in bile; hydrolysis of say -OH conjugate by beta-glucuronidase in gut will restore active drug which will be reabsorbed and produce an additional effect.


The enterohepatic shunt l.jpg

The enterohepatic shunt

Drug

Liver

Bile formation

Bile

duct

Biotransformation;

glucuronide produced

Hydrolysis by

beta glucuronidase

gall bladder

Portal circulation

Gut


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