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Absorption, distribution, metabolism and excretion

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Title: Absorption, distribution, metabolism and excretion


1
Absorption, distribution, metabolism and excretion
  • Prof. Ian Hughes, 9.83, i.e.hughes_at_leeds.ac.uk
  • 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
  • drug interactions ()
  • can enhance patient satisfaction with treatment
  • understand different dosage forms available

2
Learning objectives
  • To obtain a broad perspective over the field of
    ADME for drug molecules as a whole
  • To understand why ADME is important to drug
    action
  • To learn about the major pathways and mechanisms
    involved in ADME of drugs
  • To understand the importance of ADME to the
    dental practitioner
  • To obtain a basic knowledge about the
    quantitative aspects of ADME, pharmacokinetics

3
Overview - ADME
  • Most drugs
  • enter the body (by mouth or injection or) - must
    cross barriers to entry (skin, gut wall, alviolar
    membrane..)
  • are distributed by the blood to the site of
    action - intra- or extra- cellular - cross
    barriers to distribution (capillaries, cell
    wall.) - distribution affects concentration at
    site of action and sites of excretion and
    biotransformation
  • are biotransformed perhaps to several different
    compounds by enzymes evolved to cope with natural
    materials - this may increase, decrease or change
    drug actions
  • are excreted (by kidney or .) which removes
    them and/or their metabolites from the body
  • Pharmacokinetics is the quantification of these
    processes

4
Overview - ABSORPTION
  • Some drugs work outside the body (barrier creams,
    some laxatives) but most must
  • enter the body
  • Given by ENTERAL - oral, sublingual, buccal,
    rectal
  • PARENTERAL sc, im, iv, it
  • cross lipid barriers / cell walls
  • gut wall, capilliary wall, cell wall, blood brain
    barrier
  • ---- get into the body and (after distribution)
    to reach the cellular target ----

5
Passage through lipid membranes
  • diffusion through gaps between cells (glomerulus
    68K capillary 30K NB brain capillary - tight
    junction)
  • 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)
  • pinocytosis (insulin in CNS botulinum toxin in
    gut)
  • diffusion through lipid of cell membrane (depends
    on AREA, DIFFUSION GRADIENT, DIFFUSION
    COEFFICIENT, LIPID SOLUBILITY)

Pinocytosis
Ion channel
Diffusion
Carrier
6
Lipid solubility weak acids and weak bases
HA H A- B HCl
BH Cl-
UI I
UI
I
pKapHlog(HA/A-)
pKapHlog(BH/B)
ASPIRIN pKa 4.5 (weak acid) 100mg orally
STRYCHNINE pKa 9.5 (weak base) 100mg orally
0.1 I
99.9 I
Blood pH 7.4
Blood pH 7.4
Stomach pH 2
Stomach pH 2
UI
99.9 UI
UI
0.1 UI
Aspirin is reasonably absorbed
Strychnine not absorbed until from stomach (fast
action) enters duodenum
7
Routes of administration
  • Enteral oral, sub-lingual (buccal), rectal. Note
    soluble, enteric coated or slow release
    formulations
  • Parenteral iv, im, sc, id, it, etc. Different
    rates of absorption, different plasma peaks. Note
    iv infusors
  • Skin for local or systemic effect - note patches
  • Lungs inhalation local or systemic effect?
  • Vaginal (usually local)
  • Eye (usually local)

8
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
  • FORMULATION

9
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.

10
Bioavailability
Destroyed in gut
Not absorbed
Destroyed by gut wall
Destroyed by liver
Dose
to systemic circulation
11
Bioavailability
Plasma concentration
i.v. route
(AUC)o / (AUC)iv
oral route
Time (hours)
12
Bioequivalence steady-state digoxin
different makers products (0.25mg)
Plasma digoxin ng/ml
Maker
13
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

14
Overview - DISTRIBUTION
  • The body is a container in which a drug is
    distributed by blood (different flow to different
    organs) - but the body is not homogeneous. Note
    local delivery (asthma).
  • Volume of distribution V D/Co
  • plasma (3.5 l) extracellular fluid (14 l)
    intracellular fluid (50 l) special areas
    (foetus, brain)
  • note
  • plasma protein binding
  • tissue sequestration
  • ----- brings drug to target tissue and affects
    concentration at site of action/elimination-----

15
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
  • pH partition

16
1.5 antilog 1.5 31.6
logCt logCo - Kel . t
2.303
TIME (hours)
log plasma concentration
17
Alter plasma binding of drugs
1000 molecules
90.0
99.9
bound
100
1
molecules free
100-fold increase in free pharmacologically
active concentration at site of
action. Effective
TOXIC
18
Overview - METABOLISM
  • Drug molecules are processed by enzymes evolved
    to cope with natural compounds
  • Drug may have actions increased or decreased or
    changed
  • Individual variation genetically determined
  • May be several routes of metabolism
  • May not be what terminates drug action
  • May take place anywhere BUT liver is prime site
  • Not constant - can be changed by other drugs
    basic of many drug-drug interactions
  • metabolism is what the body does to the drug

19
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

20
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

21
The liver
Hepatocytes
smooth endoplasmic reticulum
bile
portal venous blood
microsomes
contain cytochrome P450 dependent mixed function
oxidases
systemic arterial blood
venous blood
22
Types of biotransformation reaction
  • Any structural change in a drug molecule may
    change its activity
  • Phase I - changes drugs and creates site for
    phase II
  • oxidation (adds O) eg. Microsomes (P450)
  • reduction
  • hydrolysis (eg. by plasma esterases)
  • others
  • Phase II - couples group to existing (or phase I
    formed) conjugation site
  • glucuronide (with glucuronic acid)
  • sulphate
  • others

OH
O-SO3
Phase I
Phase II
23
Cytochrome P450 dependent mixed function oxidases
DRUG
METABOLITE
DRUGO
O2
microsome
NADP
NADPH
WATER
H
There are several different types of mixed
function oxidase - different specificity
24
Genetic polymorphism in cytochrome P450 dependent
mixed function oxidases
CYP FOUR families 1-4 SIX sub-families A-F up to
TWENTY isoenzymes 1-20 CYP3A4 CYP2D6 CYP2C9
CYP2C19 CYP2A6 CYP2D617 (Thr107Ile Arg296Cys)
Caucasian 0 Africans 6 Asian 51 - reduced
affinity for substrates
25
No. of patients
Plasma conc in 267 patients after 9.8 mg/kg
isoniazid orally
0 1 2 3 Isoniazid conc. ug/ml 9 10
11 12
26
PHASE 1 reactions
Hydroxylation -CH2CH3 -CH2CH2OH
Oxidation -CH2OH -CHO -COOH
N-de-alkylation -N(CH3)2 - NHCH3
CH3OH
Oxidative deamination -CH2CHCH3
-CHCOCH3 NH3

NH2
PHASE 2 reactions
Conjugations with glucuronide, sulphate
. alters activity, made less lipid soluble so
excreted
27
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)

28
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)

29
Phase I in action
Imipramine
N
CH2 CH2 N CH3 CH3
desmethyl imipramine (antidepressant)
4-hydroxy imipramine (cardiotoxic)
30
Factors affecting biotransformation
  • race (CYP2C9 warfarin (bleeding) phenytoin
    (ataxia) Losartan (less cleared but less
    activated as well) also fast and slow isoniazid
    acetylators, fast 95 Inuit, 50 Brits, 13
    Finns, 13 Egyptians).
  • age (reduced in aged patients children)
  • sex (women slower ethanol metabilizers)
  • species (phenylbutazone 3h rabbit, 6h horse, 8h
    monkey, 18h mouse, 36h man) biotransformation
    route can change
  • clinical or physiological condition
  • other drug administration (induction (not CYP2D6
    ) or inhibition)
  • food (charcoal grill CYP1A)(grapefruit juice
    --CYP3A)
  • first-pass (pre-systemic) metabolism

31
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, carbamazepine shorten
    action of drugs or increase effects of those
    biotransformed to active agents
  • BLOCKERS acting on non-microsomal enzymes (MAOI,
    anticholinesterase drugs)

32
The enterohepatic shunt
Drug
Liver
Bile formation
Bile
duct
Biotransformation glucuronide produced
Hydrolysis by beta glucuronidase
gall bladder
Portal circulation
Gut
33
Overview - EXCRETION
  • Urine is the main but NOT the only route.
  • Glomerular filtration allows drugs 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.

34
Effect of lipid solubility and pH
ionised drug is less lipid soluble
Glomerular blood flow filtrate
99 of GF is re-absorbed concentration of drug
rises in tubule
If lipid soluble drug moves down concentration
gradient back into blood
Re-absorption
35
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.

36
Pharmacokinetics
  • Study of ADME on a quantitative basis
  • In man study blood, urine, faeces, expired air.
  • Measure urine volume concentration of drug
  • conc in urine x vol per min RENAL
  • plasma concentration CLEARANCE
  • If neither secreted nor reabsorbed then
    clearance clearance of inulin 120 ml/min
  • If completely cleared by secretion then clearance
    clearance of p-hippuric acid renal blood flow
    700 ml/min

37
Plasma concentration
-tKel
Ct Co e
lnCt lnCo - Kel t
logCt logCo - Kel . t
2.303
y c m x
38
1.5 antilog 1.5 31.6
logCt logCo - Kel . t
2.303
TIME (hours)
log plasma concentration
39
Pharmacokinetic parameters
  • Volume of distribution V DOSE / Co
  • Plasma clearance Cl Kel .V
  • plasma half-life (t1/2) directly from graph
  • or t1/2
    0.693 / Kel
  • Bioavailability (AUC)x / (AUC)iv

40
Multiple dosing
  • In a dental context some drugs are given as
    single doses. Many however are given as a course
    of therapy
  • On multiple dosing plasma concentration will rise
    and fall with each dose and will increase until
  • administration elimination
  • ie. steady state is reached.
  • At each dose the level will oscillate through a
    range
  • The objective is to remain within the therapeutic
    window, with acceptable variation at each dose
    and with a regimen which promotes compliance.

41
plasma conc
toxic
effective
Cumulation and use of loading doses
Time
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