Indian of Exper illl ental Biology

Vol. 41. ' ovclll ber 2003, pp. 1226- 1232

Review Article
Antituberculosis drug-induced hepatiti s: Risk factors ,
prevention and management
Z P Kar l & S A HlI sain
2
.*
'Departill ent of Medici ne, Maulana Azad Medi cal Coll ege. New Delhi 11 0002, I ndia
2Dcparllll ent of Bi oscience, l alllia Millia Islaillia. New Delhi 11 0025, India
Apart frolll infecti ous or viral hepatiti s. other Ill O, t comill on non-infecti ous causes of hepatiti s arc alcohol , choleslat ie.
drugs and tox ic malcri al s. The most common Ill ode lhal leads l o li ver injuri es is anl i luhercul osi s drug- induced h pati li s. The
severity of drug- induced li ver injury vari es frolll l1Iinor nonspecifi c changes in hepali c Sl ruClllre l O fulminanl hepal i e failure,
cirrhos is and li ver cancer. Pali enl S recei ving anlilubercul ar drug frequenll y devel op acul e or chroni c hepalil i<;. The li llle
requin;d ror the mctaholil es to reach hepal olOx ic level s i s much earl ier wilh i soni azid plus rifampicin lreal menl than
alonc and lhi s has been shown lO he sy nergi stic ral her lhan addilive. Anlilubercul osis drug (Arr')- i nduei bl e
cYlochromc P-4502E I (CYP2E I ) i s constitut i ve l y expressed in the li ver. Recent studi es show lhat pol Ylllorphi sm of the N-
acetyl transkrasc 2 (NAT2) genes and glutat hi one-S-t ransrCl'ase (GST) arc the Ill ajor suscept ibilit y ri sk factors for ATT-
induced hepatiti s. Thc hepatic NAT and GST arc in vol wd in the mel aboli sl1l of several carci nogeni c ary laill ines and drugs.
The NAT2 enzyllle has a gcncti c pol ymorphi sm in hUlll an. - acctyl transferase 2 genes ( AT2) have been ident i ri ed to be
responsihl e for genetic pol ymorphi slll or slow and I'apid acctylati on i n humans. Slow accty l at ors of NAT2 prove to dcvelop
Illore scvere hepatolox icit y than rapid acetylat ors making it a si gni ficant r i sk fact or. Defici ency of GST acti vil Y. hecause of
homozygous nul l mutat ions at GSTM I and GSTT I loci , Illay modulat e susceptibi l i ty to drug and xenobi otic-l ndueed
hepatot ox icit y. Pol Ylllorphi sms at GSTM I . GS'IT I ;1I1d AT2 loci had been linked to vari ous rorms of li ver injury.
including hepat ocellular carci noma.
Keywurds : Antitubercul osi s drug. Drug-induced hepati ti s, Hcpati c drug metabol i sm, Idiosyncrat ic hepalOtoxim .. Isoniazid.
Rifampi ci n. Vi ral hepatiti s
Viral hepatiti s i s a systemic in fecti on affecting
pri mari ly the li ver t. At least 8 different types of
viruses directl y associ ated with vi ral hepatiti s have
been identifi ed. The causes of hepatiti s can be broadl y
classifi ed int o infecti ous and non-infecti ous
2
. The
infect ious causes inc I ude bacteri a and more
cOlllmonl y vi ruses. The non-i n fectious causes are
al cohol (alcoholi c hepatiti s), cholcstati c, drugs and
toxic material s
3A
Apart from in l'cctious or viral hepatiti s,other most
common non- i n fcctious causes that lead to I i vel'
inj uri es are antitubercul osi s drug-i nduced hepatiti sl.2
Tubercu losi s continues to be a maj or health problem
in both devel oping and devel oped countri es because
of its resurgence in immunosuppressed pati ent s"'
Epi demiol ogi cal data suggest that antitubercul osis
drug- induced hepatiti s i s due to i ts metaboli c
idiosyncrasy rat her than direct tox icit/ . Some host
* Correspondcnt aut hor:
[ -m;l i l: ak ht arhusain2000@yah(lo.eoIrl
akhll_bi @jllli .erncl.i n
Phone : 9 1-0 11-26<)8 16 11 (R)
F;lx: 9 1-0 11 -26830337
factors that increase the hepatotoxici ty of ATT are old
age), pregnanc/ , mal nutriti onS, and concurrent
admini strati on of other drugs such as
etc. The great suscepti bi I it y of l i ver damage
to chemi cal agents (such as A drugs) i s a
consequence of its primary role in the metaboli sm of
foreign Liver injury i s present when
abnormaliti es of li ver tests i nclude an increase to
more than twi ce the upper limit or serum alani ne
amino-transferase (ALT)() 7, serum al kaline-
phosphatase (ALP/7 or bilirubin
6
.
7
.The severit y or
drug-induced li ver Injury vanes from III 111 0 1'
nonspecifi c changes in hepati c structure to fulminant
hepati c fai lure, ci rrhosi s and I i vel' cancers .The term
drug- induced li ver di sease should be confined to cases
in whi ch the nature of li ver injury has been conf irmed
hi stologi call /. Short course chemotherapy containing
i soniazid and ri fampi cin in combi nati on has proved to
be hi ghl y effecti ve in the treatment of tubercul osi s,
but one of it s adverse effects i s hepat oloxi cit /
13
.
Several reports suggest that hepatiti s i s more Frequen t
and severe with chemotherapeuti c regimens
containing both i soni azid and rifampi ci n than those
HUSSAIN et at.: ANTITUBERCULOSIS DRUG-INDUCED HEPATITIS
1227
isoniazid alone with other antitubercular drugs
6
-
IO
.
Lesobre el ai . II also described 12 cases (24%) of
jaundice with 4 deaths among 50 pati ents receiving
isoniazid and rifampicin, although many of these
patients had pre-existing liver di sease with high doses
of isoni azid and rifampicin.
Lees et al.
14
observed 4 cases (8%) of hepatiti s
among 50 patients without known liver di sease. The
hepatotoxicity of isoniazid plus rifampicin is
.. h h dd" 7 12 13 Th' . d h
synergisti c rat er t an a It I ve ' ' . IS IS ue to t e
remarkably potent inducing effect of rifampicin on the
hepatic P-4S0 mixed oxidase enzyme pathways
leading to the increased formation of toxic
intermedi ate from monoacetylhydrazine
I5
-
19
. The time
required for the toxi c metabolites (hepatotoxicity) to
reach is much earli er on isoniazid plus rifampi cin
treatment than isoniazid alone
2o
. In addition,
rifampicin can induce isoni azid hydrol ase resulting in
an increase in the formation of hydrazine from
isoni azid through the direct pathway, with consequent
manifestati on of hepatic injur/
I
-
27
. Today, we are
speaking much more of an "INH hepatotoxi city"
which is aggravated by the mi crosomal enzyme-
inducing effect of rifampicin6.23.25.2R3o. Many
questions in the pathogenesis of liver cell necros is
caused by noxae still remain open, it seems to be
certain that the damage to the membrane is the
decisive incident tri ggering the pat!iology. The
preparati on of Essentiale Forte besides vitamins
mainly contains "essential " phospholipids can
positively influence thi s damage, because
phospholipids are an integral component of the
cellular membrane systems and sub-cellular
particl es
25
. Their importance in the liver therapy
becomes obvious by their role'as structural elements,
mediators between the intracellul ar and intercellular
space, activators of different enzyme systems and III
. I' I 1';
Immuno oglca processes- .
Hepatic drug metabolism and toxic mechanisms of
liver injury
Biotransformati on reactions in liver have
traditionall y been considered protective as detoxifers
of potenti ally toxic foreign compounds
8
. Such
reactions can also convert nontoxic agents to
potenti ally toxic products
3A
.
5
. Jt has become clear that
the formation of reactive, and therefore toxic,
metabolic intermediates within the hepatocyte
accounts for injury that the liver sustains from many
of the known toxic chemicals and drugs
4
.
6
. Most drugs
and other xenobiotics that react with body tissues are
nonpolar, lipid-solubl e compounds, since absorpti on
from the intestine requires lipid solubilitl
9
.
Accordingly, biotransformation of lipid solubility to
water solubility is necessary to prevent intolerable
accumulation of foreign and endogenous molecul es
x
.
16
.
The enzyme systems responsibl e for the bi otransfor-
mation are integral parts of smooth endopl asmi c
. 8 16 f d b I'
retlclilum ' . The pathway 0 rug meta 0 Ism
divides into phases I and II. Phase J reacti ons are
largely oxidative, yielding acti ve transient metabolites.
Their reactivity serve to permit to produce hepat ic
injurl
8
.
9
. Phase 1 reactions may be regarded as
toxifi cati on reactions
6
.
8
.'J . The enzyme y tem
responsibl e for phase 1 reaction is call ed mixed
function oxidase or monooxygenase
4
. Cytochrome
P-4S0 is a key enzyme of phase I metaboli sm, a
haemoprotein located in SER
4

X
.'J. The haem-moiety
binds O
2
which is then reduced by accepting an
electron from flavoprotein reductase, the resultant
activated O
2
is incorporated into lipophili c
substances
I6
. Such activation results in the formation
of chemically reactive intermedi ates such as N-acetyl-
P-ben7.0quinoneimine (NAPQ I) as shown in Fi g. I. It
causes cell damage by per-oxidati ve damage of lipid
moi ety of bi ological membrane, forms direct co-
valent binding with protein or DNA I.I6. Co-val ent
binding of reacti ve metabolite with macromolecule
may produce injury by inactivating key enzymes or
forming protein drug adducts that are potenti al target
f
d' d " 16 PI II .
or Immune- me \ate IIlJury . l ase reacti ons
may be regarded as detoxifi cation react ions.
Conjugation with glutathione (GSH) serves to
detoxify an active intermediate as shown in Fig. 2.
Metabolism of isoniazid
Isoni azid is the maj or drug incriminated in anti -
tuberculosis drug-induced hepatotoxicitiA.6-IO.lc. IJ.
The frequency that causes 6-12% mortality if the
drugs are continued after the onset of symptoms is
typicall y between I and 36%3 1. Isoni azid (INH) gets
acetylated to acetyl isoniazid (AdNH) by N-
acetyltransferase (NAT) enzyme which I S
h
'() 16 A I' . ' d .
non epatotoxlc . cety IsonlHZI In turn gets
hydrolyzed to monoacetylhydrazine (MAH) and
isonicotini c acid (lNA)32 P-4S0-dependent hepatic
microsomal enzymes lJ .27-JO. 33-37to a potent acylating
agent that binds covalently to apparentl y vital hepatic
O
2
Acetaminophen
CYP2El
Fig. 1 - Formati on of chemicall y reaclive inlermedi ate, N-acelyl-
P- benzoquillolleiminc (NAPQ I)
1228
I DI AN J EXP 1310L, OVEMBER 2003
AIT-drug, like
Isoniazid (fNH)
N- Acetyltransferase (NAT) & other CYPs
Acetyl isoniazid (AclNH)
1
Hydrazine
(Hepatotoxic)
Phase I (Toxification)
1
MonoacetYltrlferase (MAH)
Microsomal Enzyme
CYP-4502EI
_---;.-P.:..::ha=:: se::..,;..: I1'--:---- Covalent binding
4 detoxification Toxic Metabolite_ Hepatic
GSH in presence of GST Necrosis
Removal of toxic metabolites
Fig. 2 - Digralllillalic repn:SCll lal ioll or belwcell drugs all d ell zYlll es lhal causes aillilubercu los is hepatoloxicil y
macromol ecul es and causes hepati c necrosi s can
M H
616 1J . I
convert A ' " -. A lternatI ve y MAH can be
acety lated to di acetylhydrazine (non-hepatotox ic) as
shown i n Fig. 2. I A on the other hand i s conjugated
with gl ycine to form i son icotingl ycine ( I NAG). It has
been directl y hydrol yzed by i soni azid hydrolase to
I A and hydrazine that is hepat otox ic
o
.
l
(d2
Role rifampicin
When rifampi cin IS used in combinati on with
i soniazid the inter va l bctween the commencement of
therapy and onset or hepatiti s is much short er
l 5
. This
i s due to the fact thar rirampi cin i s a known
microsomal enzyme ( P-450:?E I ) inducer
35
-:
1X
and
increases the concentrati on or tox ic mctabolites or
iSllni azid. Ran el report ed that the average
i nlerval I'm the onset or jaundice was 15.5 days in
patients treated with i soni azid and rirampi cin
Cl)mbi nat iun. whil e it was 7 1 days in the pati ent s
treat ed with i soni azid and other companion drugs. In
the study conducted by Lees el al. l.J it was round that
jaundice occurred within 7 weeks with a mode and 3
weeks in-pati ents recei ving i soni azid and rirampi cin.
Gupta el (11 ,-'.1 al so reported simil ar results wi th nearl y
all or their patient s (26 out or 29) developing hepatiti s
wi th in 2 weeks of starting therapy.
Rela/ionship of ace/yla/or sta/li s /0 hepatotoxicity of
isouiazid and rifampicin combillatio/l
I n the sllldy or i soni azi d- induced hepatiti s obser ved
that out of 2 1 patients with probabl e i soni azid li ver
injury 18(86%) WilS rapid acety lator\ although the
expectcd rrequency was 4SIJ( .\.5 Hence, they
suggesteu that isoniazid may be more hepatotox ic for
rarid acetyl ator than for sl ow acetyl ators. The rapid
acety lators mi ght be ex pected to form monoacety l -
hydrazine (MA H) from i soni aziu more rapidly than
sl ow acetylat or and MAH can be converted by hepatic
. I 2S?X-1lJ"J7 .
mlcrosoma enzymes " - . .. to a potent hepatotoxIc
agent. Thi s hypothes i s was qucsti oned on the ground
that rapid acetylat or acel yl at es MA H more rapidl y
than do slow acety l ators to the non-tox ic di acet yl -
hydrazine DA H
w
-
45
. Therefore sl ow acetylators
instead or rapid acety lator have been det ermined to
cause antitubercul osi s drug-i nduced hepatitis.J(, -.J, .
Evidence abounds from clini cal studi es that the ri sk of
hepat ic reacti ons during treatment wi th ison iazid with
or without rirampi cin i s no great er 1'0 1' rapid acety lator
than slow acet yl ator
I 1
. .JlJ-5, . A subsequent study has
shown that hepat iti s in pati ent s recei ving i sonia/.id
and rirall1picin occurred morc ort en i n slow than in
rapid acetylators. The proporti ons among those whuse
acety lator phenotype was determi ned were II Ik or
] 17 slow and I % of 244 rapid acet y latols. Recent
study shows that pol ymorphi sm or th N-acetyl-
transferase 2 ( AT2) genes are the maj or susceptibilit y
ri sk ractors
q
N-acetyltransrerase ( AT) i s one or the
major li ver enzy mes invol ved i n biotransformation of
drugs and other exogenous substances
w
. .Jo.H.J5 . .J6. AT
catal yzes the transfer of acety l group I'rom acet yl
coenzy me A to the primary amino group of the
acceptor mol ecul e, whi ch result s in the format i on of
-acetyl The hepati c (NAT) I S
invol ved in the metabol i sm or sever,t1 carci no!!eni c
aryl amines and drugs
55
Th is enzyme has a
pol ymorphi sm in human, N-acetyltransf'erase 2 genes
(NAT2) have been l ocated on chromosome 8p22.J,
5 1 5657 . d . t" lb " .
... ,I entl ICC to e responSi ble for genet ic
pol ymorphi sm of sl ow and rapid acetyiati on
5S
NAT2
i s composed of one intronl ess open reading f rame
I
'1
HUSSAI el al .. ANTITUBERCULOSIS DRUG-INDUCED HEPATITIS
l 229
(ORF) of-870-bp fragments contallling the protein
coding region of the gene
59
. Polymorphi sms in NAT2
are also associated with higher incidence of cancer
and drug Classificati on of humans as
rapid and slow acetylators i s based on hereditary
differences in rates of N-acetylation of therapeuti c
d
. . 57
an carcll10genl c agents .
Host factors: Genetic poLymorphism of humall
cytochrome P-4502El
Antitubercul osi s drug (ATT)-inducibl e cytochrome
P-4502E I (CYP2E I ) i s constitutivel y expressed in the
I
'7103517 TI b ' f'" b d d
Iver- . . ' . l e su strat e speci IClty IS roa an
includes at present at least 80 different characteri zed
substrates.19 The enzy me i s induced by a vari ety of
chemi cals, mainly substrates, and induction in these
cases IS to a maj or extent mediated at the
posttranslational level
4x
. It i s evident that CYP2EL
plays an important toxicol ogical role
3
').55. It acti vates
precarcinogens, and drugs to cytotox ic or
carcinogeni c products that mi ght be harmful and of
importance for the sy nergi sti c effect of ATT on many
f I
d' "1941475557 Th ' ..
types olver Iseases . IS reactI on IS
impli cated as being of imporrance in the eti ology of
A TT-induced li ver di sease. Because of the imporrant
tox icologi cal role of CYP2EI , a lot of research has
been conducted aimed at elucidat ing a genetic
polymorphi sm of the human CYP2E I gene and the
linkage of vari ous all eli c rorms to ditlerent types of
ATT-induced li ver di seases
61J
Restriction fragment
length polymorphi sm ( RFLP) anal ysi s of the human
CYP2EI gene reveal ed pol ymorphi sm detectabl e with
I
. . I I 6(J Th I I "
t l e restrI cti on enc onuc ease. e po y morp llC Sit s
are all present in the non-coding regions or the genc('O
The open reading frame (ORF) of the human CYP2E I
gene has been found to be well conserved, and
f
. I ' 60 l ' .
uncti ona mutati ons are very rare . wo major
pol ymorph ic sites have been st udi ed in relation to thi s
di sease. The first i s located in the 5' -flanking region
at about 1020 bp upstream
59
and in intron 6
6
0. Thi s
all ele has been seq uenced and r ou nd to carry
mutations near the promoter and in the 3' -flanking
regi on, but not in the open reading frame (ORF)(>I.
Host Jactors: Glutathione - S - trallsferase
Drug hepatotox i cit y in general , is the outcome of
dynami c processes in vol ving tox i c metabol it e
generation and its detox ifi cation in the li ver 0. 10.
Gl utathi one (GSH) plays an important protecti ve role
as an intracellular free radi ca l scavenger by
conjugating with toxi c reacti ve metabolites that are
generated from biotransformati on of drugs and
xenobiotics
62
. Sulphydryl (SH) conjugation of the
metabolites facilitates their elimination from the body,
d d I
. If ' . (;? 63 65 l ' h .
an so re uces t l e potentIa or toxICity -. '. us, It
pl ays an important role in preventing acetaminophen
and ATT-induced hepatotoxi city. Glutathi one-S-
transferase (GST) catal yze these conjugation reacti ons
and they ex i st in several i soforms with varying ti ssue-
speci fic expressi on
6J
. Defi ci ency in GST act i vit y,
because of homozygous null mutations at GSTM I and
GSTTI l oci , may modulate susceptibilit y to drug and
xenobioti c-i nduced hepatotox iCit/
5
. Some geneti c
l oci of these i soenzymes, notably GSTM I and GSTTI
are pol ymorphic
6465
Pol ymorph i sms at GSTM I ,
GSTTI and NAT2 l oci had been linked to vari ous
forms of li ver Injury, including hepatocellul ar
carci noma
65
.
66
.
J ndi viduaL risk factors
Many factors influence the ri sk of drug-induced
li ver di sease: dose
6
.
66
, blood and durati on of
intake for dose dependent hepatotox i
occasi onall y some idi osyncrati c reactions. For these
drugs, however, other host determinants are more
. I t I 8.26 X.26 t ' f' t 10.2(,
I e evan, examp es: age , sex , gene IC ac ors .
Most hepati c drug reactions are more common in
adults than in children
l8
.
19
Women are parti cularly
predi sposed to drug- induced hepatiti s
J
".
Concomitant exposllre to other agents
One drug can increase the hepatotox icit y of another
drug when admini stered concurrently, by inducing the
cytochrome P-450 (CYP) medi ated metaboli sm to
.. d' . I <1 I )7'x67
tOXIC Interme l ates e.g. acetumllloplen , a cohol - ._ C . ,
. . . d4 94 1 I . . 14 . 4
Isonl azl .. , va prolC aCl e an ti cancer drugs and
nutriti onal status
2
(, . Chroni c excessi ve alcohol
ingesti on decreases the dose threshold and enhances
the severity of acetaminophen induced hepatotoxicit/,l,
increases the ri sk and severit y of i soniazid hepatiti s.
Many ex trahepati c mani festations may be seen i n
conjugation with certain lIledi cinal agents as part of
clini cal spectrum
6
..
I
. Hallmarks of hypersensi ti vity
reactions such as fever, rash, anthralgias and
eosinophili a, point to an immunoall ergic basis of
Injur/1.64
Diagnosis of drug-induced li ver disease
Drug-i nduced liver di sease i s di scovered by fi ndi ng
abnormaliti es in hepatic associ ated enzymes" or, in
some cases, by the devel opment of hepatiti s-like
r
d' JH11 4' Th d' . f
sy mpt oms 0 jaun Ice .. -. e l agnoSlS are 0 ten
1230
INDI A J EXP BIOL, 'OVEMI:l ER 2003
based on a hi gh index of clini cal suspI cion and
whether the impli cated drugs fit the known
description has simil arl y reported cases. A temporal
relati onship i s usuall y evident with an impli cated
drug, vvith most cases of acute drug- induced li ver
di sease occurring within I week to 3 months of
exposure. A positi ve response to di scontinuing the
agent ( Ie-chall enge) cnhances the suspI cion
especiall y when the bi ochemical and clini cal
manifestations of the injury subside rapidl y. The
general rul e i s a 50% reducti on in hepatic associat ed
cnzymes after 2 weeks, with a return to normal by 4
weeks in cases of acute hepatocellul ar injury. Drugs
causing chol estati c inj ury may have a more prolonged
. (,1 . . I II
recovery Ii III . A POSl tl ve re-c 1a engc to a
suspected drug may be a definiti ve means of
confirming drug-induced li ver di sease but thi s i s
generall y not done, especiall y when dealing with
agcnt s causing hepatocellular necrosi s, because a
more severe react i on may prec ipit ate hepatic failure.
Early detection
It i s :1 criti cal point to warn patient s to rcport an)'
unt oward sy mptoms, part icularl y unexpl ained nausea,
malai se. ri ght upper quadrant abdominal pain,
lethargy or !'eve/'x. These non-speci fic fea tures may
rcpresent the prodrome of drug-induced hepatitis.
They are thc indic:llions to perform li ver tests and if
the result s suggest li ver injury, to stop treatment. A
more difficult i ssue i s protocol screeni ng \-vith li ver
te;. ts. Although often recommended by authors and
drug m:lIlufact urers. it s efficacy and cost effectiveness
arc unknown. It has been shown thalthc onset of li ver
injury i s oft en rapid, rendering monthl y or even
second screening futi !e
6
I f li ver tests are monit ored.
the Ieve! uf abnormal it y at whi ch drugs shou ld be
discontinucd i s often uncert ain. A classic::! exampl e i s
i soni azid, whi ch causes some li ver test abnormalit y in
30% of exposed subj "cts
9
Generall y. it is
rccolll mended thal the drug be stopped if ul anine
transferase (ALT) va lues exceed 250 l Ul L or more
than 5 times the upper limit of the normal, but the
prc;.ence of :Ibnormal iti es in serum bilirubin 0 :'
al bumin concentrati ons or prothrombin time provides
a clearer indi cati on to stop therap/ . Conversel y, a
ri se in GPT or minor elevati on of SAP does not
usually indicate li ver injury. Protocol screening i s not
routinely reeommended, but could be useful for
agents such as i soniazid (INI-I) because the onset of
li ver injury may be delayed and gradual in some cases
to underscore the hepatotoxi c potential of particular
drugs in the minds of pati ents and ph ys ician ' . Acti ve
management mi ght include removal of the drug and
the admini strati on of ant idotes and anti-inflammatory
d
. 1?5
an cytoprotectl ve agents' - .
Preventioll am/managemellt
With the excepti on of acetami nophcn hepat o-
tox icit y there i s littl e effecti ve treatment for drug -
induced li ver di sease. Thi s puts a spec ial onus on
preventi on and earl y detecti on of li ver injury as well
as on prompt withdrawal of the offending agent. The
majority of drugs associated with drug - induced li ver
di sease are idi osyncratic hepatotox ins
fl
.
x
.
4
. Thus, li ver
injury occurs rarel y. The overall incidence of adverse
hepati c react ions can be minimi zed onl y through
avoidance of overuse of thcse drugs
6
Simil arly,
pol ypharmacy should be avoided where pDssibl e
7
The rarit y of adverse drug react i ons also means that
the hepat otox ic potcntial of new agents may not be
recogn i zed until aft er their induct i on. Thus, all
physi cians share the responsibi l i ty to rt:port sllspeclcd
advcrse crfects to mon itoring agencics during post-
marketing surveillance Df new drugs. For those
dependent hepat otox ins, prevcnti on i " dependent on
adherence to dosage guidelines or use of blood levels.
Thi s approach has virtuall y aboli shed some forms of
drug-induced li ver injury. I n cases wi th specific ri sk
factors. strat egies 10 avoid tox icit y are essen tial.
References
I Wong W M. Wu pc. Yucn M F, Cheng C C, Yew W W.
WOll g I> C. TallO C 1'1 al ., Ant i tubcrculosi s e1rug- n:l alcd
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