Pm2 pb4toxicologylecture2011

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Drug Toxi ci t y I
Toxi col ogy:
Mol ecul ar Mechani sms
Gar y St ephens
Room 208 Hopki ns
g. j . st ephens@r eadi ng. ac. uk

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Af t er t hi s l ect ur e, and f ur t her r eadi ng as
r equi r ed, st udent s wi l l be abl e t o:
• expl ai n how dr ugs ar e i mpor t ant agent s f or
poi soni ng
• descr i be t he mani f est at i ons of t oxi ci t y
• out l i ne t he maj or mol ecul ar mechani sms of
t oxi ci t y and how dr ug met abol i t es may be
t oxi c
• expl ai n how t oxi c pot ent i al of a dr ug can
be quant i f i ed usi ng a var i et y of met hods
i ncl udi ng car ci nogeni ci t y, mut ageni ci t y,
t er at ogeni ci t y, al l er gy t est i ng
• expl ai n LD50 val ues and t her apeut i c i ndex
Lect ure obj ect i ves

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Pharmacol ogy:
t he st udy of t he ef f ect of dr ugs on t he
f unct i on of l i vi ng syst ems
[ or i gi n: Gk p ha r ma ko n = dr ug]
gy:
y of t he ef f ect of poi sons on t he f unct i on of l i vi ng sy
Chemi cal agent s t hat cause t oxi ci t y i ncl ude:
• Dr ugs
• I nsect i ci des/ her bi ci des
• Pl ant t oxi ns
• Ani mal t oxi ns
• Chemi cal weapons
• Radi oact i ve el ement s

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Par acel sus ( 1493- 1541)
‘ Gr andf at her of
Toxi col ogy’
“The dose makes t he
poi son”
" Al l t hi ngs ar e poi son
and not hi ng i s wi t hout
poi son, onl y t he dose
per mi t s somet hi ng not
t o be poi sonous. "
t her apeut i c
ef f ect
t oxi c
ef f ecti ncr easi ng dose

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Adverse Drugs React i ons ( ADRs)
ADRs ar e noxi ous or uni nt ended r esponses occur r i ng
at t herapeut i c doses ( WHO def i ni t i on) ~ 5% of al l
acut e hospi t al admi ssi ons
Type A
( augment e
d) ADRs
Ef f ect s ar e:
∙ r el at ed t o known
phar macol ogy, but
undesi r abl e
∙ common, dose-
r el at ed
∙ pr edi ct abl e
Exampl es
∙ haemor r hage wi t h
ant i coagul ant s
∙ r espi r at or y depr essi on wi t h
opi oi ds
∙ sedat i on wi t h anxi ol yt i c
and ol der ant i hi st ami ne dr ugs
Type B
( bi zar r e)
ADRs
Ef f ect s ar e:
∙ unr el at ed t o
known phar macol ogy
∙ r ar e
∙ unpr edi ct abl e
∙ of t en
i di osyncr at i c
Exampl es
∙ anaphyl axi s wi t h peni ci l l i n
∙ al l er gi c l i ver damage by
hal ot hane
∙ bone mar r ow suppr essi on by
chl or ampheni col
∙ i ndi vi dual al l er gy/ genet i c
basi s

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t he ef f ect s of t he body on t he poi son
( r el at es t o Absor pt i on, Di st r i but i on, Met abol i sm,
Excr et i on ( ADME) ) .
Wi t h t hi s i nf or mat i on i t i s possi bl e t o pr edi ct
concent r at i on of t oxi n t hat r eaches t he si t e of i nj ur y
and t he r esul t i ng damage.
orpt i on i ngest i on mer cur y and di oxi n i n f i sh
pest i ci des i n pr oduce
sal monel l a ( di ar y) , bot ul i num ( meat ) t ox
i nhal at i on asbest os, ner ve gases
t ri but i on as di scussed f or t her apeut i c dr ugs
Toxi coki net i cs

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Met abol i sm Phase I by cyt ochr ome P450 ( oxi dat i on,
r educt i on, hydr ol ysi s)
Phase I I conj ugat i on t o al l ow excr et i on i n
ur i ne and bi l e
Det oxi f i cat i on: compound r ender ed l ess t oxi c
Toxi f i cat i on: r el at i vel y i ner t compound
conver t ed i nt o t oxi n
Excret i on t oxi ns not excr et ed may be st or ed i n:
bone ( eg. l ead)
f at ( eg. DDE a met abol i t e of t he pest i ci de
DDT di chl or odi phenyl
t r i chl or oet hane)
The t oxi n may be r el eased sl owl y i nt o t he
body
Toxi coki net i cs

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Mol ecul ar Mechani sms of Toxi col ogy
1. Al l ergi c responses
Common f or m of ADR, usual l y wi t h a di f f er ent t i me
cour se t o phar macol ogi cal ef f ect s
4 basi c cl i ni cal syndr omes – t ypes I , I I , I I I & I V
( Gel l & Combes, 1963)
Type I hypersensi t i vi t y react i on – I gE- medi at ed mast
cel l degr anul at i on
Type II ant i body- medi at ed cyt ot oxi c
hypersensi t i vi t y-
i nvol ve haemat ol ogi cal r eact i ons i . e. t hose
per t ai ni ng t o t he bl ood cel l s
and bl ood- f or mi ng or gans
Type I I I i mmune compl ex- medi at ed hyper sensi t i vi t y

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Type I hypersensi t i vi t y react i ons can t ri gger
anaphyl act i c shock
1 2
l ow MW al l er gen
( eg. bee venom,
peanut oi l )
i mmunogeni c
conj ugat e
eg.
peni ci l l i n
75% of al l
deat hs
hapt en
mast cel l
I gE r ecogni t i on
t r i gger s
hi st ami ne r el ease
br onchoconst r i ct i on
vasodi l at i on
i nf l ammat i on
t r eat ed wi t h
adr enal i ne

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Type II hypersensi t i vi t y react i ons depl et e
bl ood cel l t ypes
These r eact i ons can depl et e:
Red bl ood cel l s ( haemol yt i c anaemi a) eg.
sul f onami des
Neut r ophi l es ( agr anul ocyt osi s) eg. cer t ai n
NSAI Ds
T cel l
bl ood cel l
eg. RBC
ant i gen-
bound RBC
cyt ot oxi c T
cel l - medi at ed
cel l l ysi s
I gG- bound
RBC
Cel l l ysi s
1.
t oxi n
ant i gen
2. 3.
compl ement -
medi at ed l ysi s

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2. Recept or, i on channel and enzyme- medi at ed
t oxi ci t y
Mol ecul ar drug/t oxi n t arget s
Recept ors ( 4 maj or super f ami l i es)
∙ Li gand- gat ed i on channel s i onot r opi c
r ecept or s
vol t age- gat ed i on channel s
∙ GPCRs - G prot ei n coupl ed recept ors
( met abot r opi c r ecept or s)
∙ Enzyme- l i nked recept ors ( t yr osi ne ki nase
act i vi t y)
∙ Nucl ear recept ors ( r egul at e gene t r anscr i pt i on)
Enzymes met abol i c and cat abol i c pat hways
Carri ers upt ake/ t r anspor t syst ems

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Sources of t oxi ns
Source Act i ve
agent
Mechani sm of
act i on
Pl ant s
Ama ni t a
p ha l l o i d e s
α- amani t i n i nhi bi t s RNA
pol ymer ase
Di g i t a l i s l a na t a di goxi n/ di gi t
oxi n
Na+
/ K+
ATPase
i nhi bi t or
Cal abar ( or deal )
bean
physost i gmi ne ant i chol i nest er ase
At r o p i ne
be l l a d o nna
at r opi ne bl ocks muscar i ni c
AChR
Bact eri a

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Ani mal sources of venoms and t oxi ns
Source Act i ve agent Mechani sm of act i on
Kr ai t s ( el api d
snakes)
α- bungar ot oxi n bl ocks ni cot i ni c AChR
Gr een mamba snakes dendr ot oxi ns bl ock K+
channel s
Funnel web spi der ω- agat oxi n bl ocks CaV2. 1 Ca2+
channel s
Coneshel l ω- conot oxi n bl ocks CaV2. 2 Ca2+
channel s
Tar ant ul a spi der SNX- 482 bl ocks CaV2. 3 Ca2+
channel s
Puf f er f i sh t et r odot oxi n bl ocks Na+
channel s
Fr og ( De nd r o ba t e s )
ski n
car di ac
gl ycosi des
Na+
/ K+
ATPase i nhi bi t or

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ni mal t oxi ns bl ock i on- conduct i on
gar ot oxi n on ni cot i ni c acet yl chol i ne r ecept or ( nACh
r ecept or gat e ( α hel i ces)
ACh ACh
Na+
Banded kr ai t
( Bung a r us mul t i c i nc t us )
α- bungar ot oxi n

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t age- gat ed K+
channel s are bl ocked by dendrot oxi ns
dendr ot oxi ns
Bl ack mamba
De nd r o a s p i s p o l y l e p i s )
Gr een mamba
( De nd r o a s p i s
a ng us t i c e p s )

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age- gat ed Ca2+
channel s are i mport ant t oxi n t arget s
Funnel web spi der Coneshel l Tar ant ul a spi der
ω- agat oxi n
( CaV2. 1)
ω−conot oxi n
( CaV2. 2)
SNX- 482
( CaV2. 3)
Ca2+
cur r ent
r ecor di ng f r om a
sensor y neur on i n
pai n pat hway ( Wi l son
e t a l . 2001)
ω- conot oxi n
ω- agat oxi n
SNX- 482
Current(pA)

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odot oxi n act s on Na+
channel s t o bl ock act i on pot ent
Puf f er f i sh Tet r odot oxi n ( TTX)

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“ You ar e wal ki ng t hr ough a cr owded shoppi ng
mal l , when you hear a sof t ‘ pop’ and see smoke
comi ng f r om t he ot her end of t he mal l . You
i mmedi at el y not i ce di m vi si on, and your nose
begi ns t o r un sever el y. Less t han 1 mi nut e
l at er , you not i ce shopper s col l apsi ng t o t he
f l oor , br eat hi ng heavi l y, some of t hem l osi ng
consci ousness and devel opi ng sei zur e act i vi t y.
You not i ce t hat t hat t hei r pupi l s ar e
const r i ct ed. You i mmedi at el y gr ab 2 smal l
chi l dr en near you, cover your nose and mout h
wi t h your j acket , and r un out of t he mal l ”
l . Jonat han Newmar k, Ar c h Ne ur o l . 2004; 61: 649- 652
Ar my Medi cal Resear ch I nst i t ut e of Chemi cal Def ense
Enzyme- medi at ed t oxi col ogy

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ersi bl e ant i chol i nest erase eg. parat hi on and sari n
P OR2R1
X
O
N
N
ser i ne
O
gl ut amat e
COO-
hi st i di ne
O
P
OR2
R1
N
N
ser i ne
HO
gl ut amat e
COO-
hi st i di ne
cat al yt i c
si t e
ani oni
c
si t e
no hydr ol ysi s- d e no v o
synt hesi s needed
enzyme
act i ve si t e

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i mes are st rong nucl eophi l es t hat react i vat e AChest erase
N
N
ser i ne
O
gl ut amat e
COO-
hi st i di ne
O
P
OR2
R1
HO N
N+
O N
N+
P
OR2
R1
O
pr al i doxi me
N
N
ser i ne
HO
gl ut amat e
COO-
hi st i di ne
cat al yt i c
si t e
ani oni
c
si t e

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l i ne of def ence agai nst bi ol ogi cal nerve gases :
opi ne- mAChR bl ocker - cent r al r espi r at or y depr essi on
al i doxi me- r eact i vat i on of acet yl chol i nest er ase
React i vat i on of pl asma chol i nest er ase ( ChE) i n a vol unt eer
subj ect by i nt r avenous i nj ect i on of pr al i doxi me. ( Si m V M
1965 J Am Med Assoc 192: 404. )

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3. Bi ochemi cal pat hways
( i ) Cyani de i nhi bi t s mi t ochondr i al cyt ochrome c oxi dase t o
pr event cel l ul ar r espi r at i on
( i i ) Car bon monoxi de: di spl aces oxygen f r om haemogl obi n
causi ng hypoxi a

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4. Organ- Di rect ed Toxi ci t y
Organs part i cul arl y suscept i bl e t o t oxi n damage are
t he l i ver
and ki dney
Hepat ot oxi ci t y
(i) hepat i c necrosi s
par acet amol poi soni ng
(ii) hepat i c i nf l ammat i on ( hepat i t i s)
hal ot hane can coval ent l y bi nd t o l i ver pr ot ei ns
t o t r i gger an aut oi mmune r eact i on
(iii) chroni c l i ver damage ( ci rrhosi s)
l ong- t er m et hanol abuse causes cel l ul ar t oxi ci t y
and i nf l ammat i on and mal nut r i t i on as et hanol

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acet amol i s a promi nent cause of hepat i c poi soni ng
% of al l poi son admi ssi ons and >200 deat hs/year)
Tr eat ment :
Acet yl cyst ei ne
Met hi oni ne
( gl ut at hi one pr ecur sor s)
par acet amol
O
NH
OH+
Phase I Igl ucur oni de
or sul phat e
conj ugat i on
( ~90%)
hepat ot oxi c
( bi nds t o pr ot ei n
t hi ol gr oups)
Phase I
O
O
N
N- acet yl - p - benzoqui nonei mi ne
( NAPQI )
( ~10%)
( non-
t oxi c)
gl ut at hi o
ne
conj ugat i
on
excr et i on
Phase I I
ver dose:
i ) enzymes sat ur at i on
i i ) gl ut at hi one depl et i on

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Organ- Di rect ed Toxi ci t y
Nephrot oxi ci t y
( i ) changes i n gl omerul ar f i l rat i on rat e ( GFR)
Lar gel y due t o dr ugs t hat al t er bl ood f l ow :
NSAI Ds ( eg. aspi r i n) r educe pr ost agl andi ns
whi ch i n t ur n r educes bl ood f l ow/ GFR
ACE i nhi bi t or s ( eg. r ami pr i l ) i ncr ease bl ood
f l ow/ GFR
( i i ) al l ergi c nephri t i s
al l er gi c r eact i on t o NSAI Ds ( eg. f enopr of en)
and ant i bi ot i cs ( eg. met aci l l i n)
( i i i ) chroni c nephri t i s
l ong- t er m NSAI D and par acet amol use

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5. Mut agenesi s and carci nogenesi s
Mut agens cause changes t o cel l DNA t hat ar e
passed on when cel l di vi des, i f t hi s pr oduces a
neopl ast i c cel l t he agent i s t er med a
carci nogen.
2 maj or cl asses of gene ar e i nvol ved i n
car ci nogenesi s:
• Prot o- oncogenes: pr omot e cel l cycl e
pr ogr essi on
eg. const i t ut i ve act i vi t y of gr owt h f act or
t yr osi ne- ki nase r ecept or s can cause neopl ast i c
t r ansf or mat i on
• Tumour- suppressor genes: i nhi bi t cel l cycl e

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6. Terat ogeni ci t y
Thal i domi de
( R) - enant i omer
sedat i ve
Thal i domi de
( S) - enant i omer
t erat ogen
Terat ogenesi s: t he cr eat i on of bi r t h def ect s dur i ng
f et al devel opment
Terat ogens: subst ances t hat i nduce bi r t h def ect s

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• 1950’ s- t hal i domi de was synt hesi zed by t he
Grünent hal
• Non- t oxi c at hi gh doses i n al l ani mal s speci es
t est ed
• 1957 - mar ket ed t hr oughout Eur ope i n as
Cont ergan a non- l et hal hypnot i c and sedat i ve,
r ecommended as an ant i - emet i c t o t r eat mor ni ng
si ckness i n pregnant women
• 1961 - t hal i domi de was t he best - sel l i ng
sl eepi ng pi l l i n West Ger many and t he UK
• However , t hal i domi de pr oduced t er at ogeni c
The t hal i domi de di sast er heral ded modern
t erat ogeni ci t y t est i ng

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• An est i mat ed 8- 12, 000 i nf ant s wer e bor n wi t h
def or mi t i es caused by t hal i domi de, and onl y
about 5, 000 of t hese sur vi ved beyond chi l dhood
• 1968 - Cont ergan case was br ought t o t r i al
• 1970 - cour t di smi ssed t he case due t o onl y
mi nor r esponsi bi l i t y of Grünent hal and " mi nor
i mpor t ance t o t he publ i c of t he Feder al Republ i c
of Ger many"
• I n f act , t hal i domi de i s a usef ul dr ug, used
t oday t o t r eat l eprosy and mul t i pl e myel oma
( pr obabl y due t o i nhi bi t or y act i vi t y on t umour
necr osi s f act or ( TNF) - α pr oduct i on)
The t hal i domi de di sast er heral ded modern
t erat ogeni ci t y t est i ng

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Drug ef f ect s on f et al devel opment
St age Gest at i on
per i od
Cel l ul ar
pr ocess
Af f ect ed by
Bl ast ocyt e
f or mat i on
0- 16 days Cel l di vi si on Cyt ot oxi c
dr ugs
Al cohol
Or ganogenesi
s
~17- 60
days
Di vi si on
mi gr at i on
di f f er ent i at i
on deat h
Ter at ogens
( t hal i domi de
,
r et i noi ds
ant i epi l et i c
s
war f ar i n)
Mat ur at i on >60 days As above Al cohol
Ni cot i ne
ACE

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Drug Toxi ci t y II
Toxi col ogy:
Treat ment and prevent i on

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St ages of drug devel opment
g di scover y phar macol ogi cal sel ect i on
ecl i ni cal devel opment t oxi ci t y t est i ng
ase I t est i n heal t hy ( ~20- 80) vol unt eer s
ase I I smal l scal e t est i n ( ~100- 300) pat i ent s
ase I I I l ar ge scal e ( ~1000- 5000) cont r ol l ed t r i
ase I V post - mar ket i ng sur vei l l ance
~50 pr oj ect s
1
12
5
3
1.
7
2- 5
~2
5- 7
year s

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St ages of drug devel opment
Phase I
100 – 200
Healthy Subjects
• Does it seem safe in humans?
• What does the body do to the drug
(pharmacokinetics)?
• What does the drug do to the body
(pharmacodynamics)?
• Might it work in patients?
Phase II 200 – 300
Patients
• Does it seem safe in patients?
• Does it seem to work in patients?
Phase III 1,000 – 3,000
Patients
• Does it seem safe in patients?
• Does it really work?
Phase IIIb Hundreds -
Thousands
Patients
• Does it seem safe in a different
group of patients?
• Does it really work in a different
group of patients?
Phase IV Tens to many
thousands
Patients
• Is it truly safe?
• How does it compare with similar
drugs?

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Precl i ni cal drug devel opment
t est i ng
To assess genot oxi c pot ent i al a bat t ery of
t est s are used:
i n vi t ro t est s f or mut ageni ci t y eg Ames t est
• st r ai ns of Sa l mo ne l l a t y p hi mur i um bact er i a
cannot synt hesi s hi st i di ne
• mut ant gr own on hi st i di ne- cont ai ni ng medi a
• drug and a l i ver mi cr osomal enzyme
pr epar at i on ( t o t est f or r eact i ve
met abol i t es) added
• hi st i di ne becomes depl et ed and onl y back-
mut ant s can gr ow
• mut at i on r at e measur ed

35
Precl i ni cal drug devel opment
t est i ng
i n vi t ro cyt ogenet i c eval uat i on of
chromosome damage i n r esponse t o dr ug
• carci nogeni ci t y t est i ng:
chr oni c dr ug dosi ng; l ook f or t umour s
• reproduct i ve ( t erat ogeni ci t y) t est i ng:
pr egnant f emal es f r om one r odent speci es and
one non- r odent ( usual l y r abbi t ) speci es
dosed wi t h dr ug at di f f er ent or ganogenesi s
st ages out l i ned pr evi ousl y; l ook f or bi r t h
def ect s

36
Prel i mi nary t oxi ci t y
t est i ngum non- t oxi c dose ( gi ven f or 28 days t o 2 speci es) .
s exami ned post - mor t em and t i ssue damaged assessed
dose LD50 - t he dose of dr ug whi ch ki l l s 50% of t r eat ed
s wi t hi n a speci f i ed shor t amount of t i me
LD50
l og [ dr ug] ( M)
Toxicresponse
-9 -8 -7 -6 -5 -4 -3
0
25
50
75
100

37
t est i ng
NOAEL
LOAEL
EL ( no obser ved adver se ef f ect s l evel )
est concent r at i on t hat does not a t oxi c r esponse
EL- l owest obser ved adver se ef f ect s l evel
st concent r at i on t hat pr oduces a t oxi c r esponse
l og [ dr ug] ( M)
Toxicresponse
-9 -8 -7 -6 -5 -4 -3
0
25
50
75
100

38
t est i ngEL ( no obser ved adver se ef f ect s l evel )
hest concent r at i on t hat does not a t oxi c r esponse
1. Det er mi ne NOAEL
2. Conver t NOAEL t o a ‘ Human
Equi val ent Dose’ ( HED)
• Adj ust f or ant i ci pat ed
exposur e i n humans
• Adj ust f or i nt er - speci es
di f f er ence i n af f i ni t y
and pot ency
3. Appl y >10 f ol d saf et y f act or

39
t est i ng
Cal cul at i ng HED ( Human Equi val ent Dose)
NOAEL: dog 50 mg/ kg

40
LD50 val ues f or di f f erent
t oxi nsToxi ci t y rat i ng Exampl e LD50 ( mg/kg)
Sl i ght l y t oxi c
( 5- 15 g/ kg)
Et hanol 8000
Moder at el y t oxi c
( 0. 5- 5 g/ kg)
Sodi um chl or i de
Par at hi on
4000
1300
Ver y t oxi c
( 50- 500 mg/ kg)
Aspi r i n
Par acet amol
300
300
Ext r emel y t oxi c
( 5- 50 mg/ kg)
Theophyl l i ne
Di phenhydr ami ne
50
25
Super Toxi c
( <5 mg/ kg)
Pot assi um
cynani de
Di goxi n
Tet r odot oxi n
Bot ul i num t oxi n
3
0. 2
0. 01
0. 00001 ( 10
ng/ kg ! )

4141
Therapeut i c i ndex
The rat i o of t he dose of t he drug t hat
produces an unwant ed
( t oxi c) ef f ect t o t hat produci ng a want ed
( t herapeut i c) ef f ect
= LD50 / ED50
response(%)
l og [ dr ug] ( M)
Smal l TI: e. g.
warf ari n
response(%)
l og [ dr ug] ( M)
Large TI: e. g.
peni ci l l i n, aspi ri n
Therapeut i c wi ndow Therapeut i c wi ndow

42
Prel i mi nary t oxi ci t y t est i ng
The or al LD50 of a new dr ug was det er mi ned i n r at s.
Q. What can t hi s val ue t el l us:
A. Shor t t er m, l et hal ef f ect s
B. Long- t er m, l et hal ef f ect s
C. Long- t er m, non- l et hal ef f ect s
D. Pot ent i al Type B adver se dr ug r eact i ons
E. Let hal dosage when i nj ect ed
F. Toxi ci t y i n young and ol d humans

43
The El i xi r Sul f ani l ami de di sast er of 1937 was one of
t he most consequent i al mass poi soni ngs of t he 20t h
cent ur y.
Sul f ani l ami de was di l ut ed i n di et hyl ene gl ycol t o
gi ve a r ed El i xi r Sul f ani l ami de.
One hundr ed and f i ve pat i ent s di ed f r om i t s
t her apeut i c use.
Under t he exi st i ng dr ug r egul at i ons, pr emar ket i ng
t oxi ci t y t est i ng was not r equi r ed.
I n r eact i on, t he U. S. Congr ess passed t he 1938
Federal Food, Drug and Cosmet i c Act , whi ch r equi r ed
pr oof of saf et y bef or e t he r el ease of a new dr ug.
Why do we need toxicity testing……..

44
The TGN1412 di sast er has hi ghl i ght ed
need f or
accurat e t oxi ci t y t est i ng
• TGN1412 i s a monocl onal ant i body ( MAB) desi gned
t o bi nd CD28 pr ot ei n t o act i vat e l eucocyt es
• TGN1412 coul d f i ght l eukaemi a by t r i gger i ng
cyt oki ne r el ease
• Ani mal st udi es of TGN1412 i ndi cat ed no t oxi ci t y
• 6 vol unt eer s wer e gi ven 1: 500 di l ut i ons of doses
used i n ani mal st udi es at 30 mi nut e i nt er val s
accor di ng t o agr eed pr ot ocol s.
A f ur t her 2 vol unt eer s r ecei ved a pl acebo
• Wi t hi n mi nut es of t he 6t h
vol unt eer r ecei vi ng t he

45
Pot ent i al f l aws i n t he TGN1412 st udy
• Lack of bi ol ogi cal knowl edge ( of how CD28 wor ks)
• Use of heal t hy vol unt eer s wi t h i nt act i mmune
r esponse coul d t r i gger a ‘ cyt oki ne st or m’
• TGN1412 wor ks di f f er ent l y bet ween speci es ( mai nl y
human pr ot ei n)
• Dose r egi me t oo shor t ( i . e gi ven t oo f r equent l y)
• Test i ng shoul d have been st agger ed over sever al
days
• Pr obl em wi t h cont ami nant s i n f or mul at i on ( l at er
di scount ed)
• Suggest ed i mpr ovement : Bl i st er t est - expose smal l

46
Summary: Treat ment and prevent i on of
t oxi ci t y
1. Pr ecl i ni cal t oxi ci t y t est i ng i s a vi t al par t
of dr ug devel opment
2. New compounds must be assessed i n par t i cul ar
f or mut ageni c, car ci nogeni c and t er at ogeni c
pot ent i al
3. Pr el i mi nar y t oxi ci t y t est i ng t ypi cal l y uses
LD50 and NOAEL, LOAEL val ues
4. LD50 exper i ment s ar e not per f ect
5. Prevent i on of t oxi ci t y i s based on knowl edge
of mol ecul ar mechani sms of t oxi n act i on

Pm2 pb4toxicologylecture2011

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