Download Absorption, distribution, metabolism and excretion

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
– drug interactions (*******)
• can enhance patient satisfaction with treatment
• understand different dosage forms available
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
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 extracellular - 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
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 ----
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; LDOPA 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)
Ion
channel
Carrier
Pinocytosis
Diffusion
Lipid solubility :weak acids and weak bases
HA <==> H+ + A[ UI ]
[I]
pKa=pH+log(HA/A-)
ASPIRIN pKa = 4.5 (weak acid)
100mg orally
0.1 = [ I ]
Stomach
pH = 2
99.9 = [ UI ]
Blood
pH = 7.4
[ UI ]
Aspirin is reasonably absorbed
from stomach (fast action)
B + HCl <==> BH+ + Cl[ UI ]
[I]
pKa=pH+log(BH+/B)
STRYCHNINE pKa = 9.5 (weak base)
100mg orally
99.9 = [ I ]
Stomach
pH = 2
0.1 = [ UI ]
Blood
pH = 7.4
[ UI ]
Strychnine not absorbed until
enters duodenum
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)
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
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.
Bioavailability
Destroyed
in gut
Dose
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation
Bioavailability
Plasma
concentration
70
60
i.v. route
50
(AUC)o / (AUC)iv
40
oral route
30
20
Time (hours)
10
0
0
1
2
3
4
5
6
7
8
9
Plasma digoxin
ng/ml
Bioequivalence: steady-state digoxin:
different maker’s products (0.25mg)
3.5
3
2.5
2
1.5
1
0.5
0
1
2
3
4
Maker
5
6
7
8
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
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-----
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
=1.5; antilog 1.5 = 31.6
1.6
logCt = logCo - Kel . t
2.303
1.1
0.6
TIME (hours)
0.1
0
5
-0.4
log plasma
-0.9 concentration
10
15
20
Alter plasma binding of drugs
1000 molecules
99.9
% bound
90.0
1
molecules free
100
100-fold increase in free pharmacologically
active concentration at site of action.
Effective
TOXIC
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
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
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
Hepatocytes
portal
venous
blood
systemic
arterial
blood
smooth
endoplasmic
reticulum
bile
microsomes contain cytochrome P450
dependent
mixed function oxidases
venous blood
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
Phase I
Phase II
O-SO3
Cytochrome P450 dependent
mixed function oxidases
DRUG
METABOLITE
=DRUG+O
O2
microsome
NADPH
H+
NADP+
WATER
There are several different types of mixed
function oxidase - different specificity
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
CYP2D6*17 (Thr107Ile; Arg296Cys) Caucasian 0%
Africans 6% Asian 51% - reduced affinity for
substrates
No. of patients
25
Plasma conc in 267 patients after
9.8 mg/kg isoniazid orally
20
15
10
5
0
0
1
2
3 Isoniazid conc. ug/ml 9
10
11
12
PHASE 1 reactions
Hydroxylation -CH2CH3
Oxidation -CH2OH
N-de-alkylation -N(CH3)2
-CH2CH2OH
-CHO
-COOH
- NHCH3 + CH3OH
Oxidative deamination -CH2CHCH3
-CHCOCH3
+
NH3
|
NH2
PHASE 2 reactions
Conjugations with glucuronide, sulphate
…. alters activity, made less lipid soluble so excreted
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)
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)
Phase I in action
Imipramine
4-hydroxy
imipramine
(cardiotoxic)
N
CH2
CH2
N
CH3 CH3
desmethyl
imipramine
(antidepressant)
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
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)
The enterohepatic shunt
Drug
Liver
Bile formation
Bile
duct
Hydrolysis by
beta glucuronidase
Biotransformation;
gall bladder glucuronide produced
Portal circulation
Gut
Overview - EXCRETION
• Urine is the main but NOT the only route.
• 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.
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
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.
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
Plasma concentration
14
Ct = Co e-tKel
lnCt = lnCo - Kel t
12
10
8
logCt = logCo - Kel . t
2.303
6
y
4
=
c
m
x
2
0
0
2
4
6
8
10
12
TIME (hours)
14
16
18
20
1.6
=1.5; antilog 1.5 = 31.6
logCt = logCo - Kel . t
2.303
1.1
0.6
TIME (hours)
0.1
0
2
4
6
8
-0.4
-0.9
log plasma
concentration
10
12
14
16
18
20
Pharmacokinetic parameters
• Volume of distribution
• Plasma clearance
V = DOSE / Co
Cl = Kel .V
• plasma half-life (t1/2)
or
directly from graph
t1/2 = 0.693 / Kel
• Bioavailability
(AUC)x / (AUC)iv
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.
plasma conc
toxic
7
6
5
effective
4
Cumulation and use of
loading doses
3
2
1
Time
0
0
5
10
15
20
25
30