I Chapter Pharmacokinetics: Metabolism

~\
I
-,\
~
and Excretion of Drugs, Kinetics A
of Elimination
- BIOTRANSFORMATION
{Metabolism)
Biotransformation means chemical alteration of
the drug in the body.· lt is needed to render

iii ·M•-
1 Chloral h~drate
Mor-phlne
Cefotaxime
Allopurinol

1 '
-

-
-

·i@c&Miii-lllla
Trichloroethanol ~
Morpnrne-6-glucuronide
Desacetyl cefotaxime
Alloxanthine

.
nonpolar (lipid-soluble) compounds polar (lipid- Procainamide - N-acetyl procainamide
insoluhle) so that :they 7ire ~ s o ~ in the Primidone Phenobarbitone,
phenylethylrnalonamide
renal tubules a~d are excreted. Most hydrophilic Desmethyl-diazepam,
Diazepam
drugs, e.g. slreptomyciln, _eosti mine, pab.Ql(o- oxazepam
nium._ etc. are little foo'fi'.ansfor 1d a·. 1,argyly Digitoxin Digoxin
" '"'-
- ~
excret~d unchanged. Mechanisms which meta- lmipramine Desipramine
Amitriptyline Nortriptyline
bolize d ~ t i a l l y foreign substances) have Morphine
Codeine
developed to protect the body from ingested Spironolactone Canrenone
toxins. Losartan E 3174
The primary site for drug.metabolism is -~
others are-kidney, intestine, lungs and plasma. Biotransformation reactions can be classified
Biotransformation of drugs may lead to the into:
following.
(a) Nonsynthetic/Phase l/Functionalization reac-
(i) . Inactivation Most -drugs and ~!_l"_ active tions: a functional group is generated or exposed-
metabolites are rendereo mactive or less active, metabolite may be active or inactive':-
e.g. ibuprofen, paracetamol, lidocaine, ~mp-
henicol, pr-opranoiolairid .its a~~ (b) Synthetic/Cou,iugation/ Phase II reactions: an
r
~ ! o h - -~ endogenous radical is conjugated tq_Jhe.._drng-
metal5olite is mostly-T11.acdve ; except -fe~ dn~gs,
(ii) Acti,ve metabolitf.~ from an active drug - . ---.. _. -..;:-- ~ -.- - --
e.g. glucuronide con1ngate of morphine and st~lf_c1Je
Many drugs have been found to be partially , conj~of minoxidil are active: ----- .
converted to one or more active metabolite; the
effects observed are the sumtotal of that due to Nonsynthetic~.~~ctions
the parent drug and its active metabolite(s) (see
box). (i) Oxidation This reaction i~~
of oxygen/negatively charged radical or rem~ al
(iii) Activation of inactive drug Few drugs are of hydrogen/positively charged radical. oxiaftrons
in~_!!~~~ch and need conversi_~n in the body anhh-e ·-m'osf important drug metabolizing reac-
to oi:i_e__2[. more active ~meta15ollies. ,Suclta- drug tions. Various oxidation reactions are:
is calle~ _~_P1.'CJ!1r_ug (see box). The prodrug may
~ydroxylation; oxxgenation at C, Nor S ~~o.ms;
offer advantages over the active form in being
N or O-~ylation, oxidative deamination,
more stable, having better bioavailability or other etc.
desirable pharm?cokinetic properties or less side
i , In many cases the i_!!itial insertip n ofox~g~}
effects and toxicity. Some prodr-ugs are activated
selectively at the site of action. atom i_!:}~ the dr!1g1n.QJ.ec.ule produ<;es shor~e
--
highly reactive quinone/epoxide~e
 ' ~\\
!
INATION
OF DRUGS, KINETICS OF ELIM
METABOLISM AND EXCRETION
rtant CYP isoform whi~h
Prodrug Actwe form CYP2D6 This is the next most impo
including tricyclic antide~ -
metabolizes nearly 20% drugs
Dopamine e inhibitors, many neuro-
Levodopa sants , selective serotonin ~ uptak
Enalapril Enalaprilat ers and opiates. ffinioi"fion bf
leptics, antiarrhythmic s, ~-block
a-Methyldopa a-methylnorepinephdne ts in failure of conversion of
tfrls enzyme• by qum,aine resuf
effect of codeine is lost.
Dipivefrine Epinephrine codeine to morphine ➔ analgesic
ed into 'extensive' or 'poor'
Sulindac Sulfide metabolite Human subjects can be group
debrisoquin. The poor
Proguanil Cycloguanil metabolizers of metoprolol and
206 enzyme and exhibit low
Prednisolone metabolizers have an altered CYP
Prednisone . .
capacity to hydroxylate many drugs
Bacampicillin Ampicillin
biotransformation of > 15
~~lfasala:zine 5-Aminosallcylic.acid CYP2C8/9 Important in the
ph_~_nytoi~.!..._cafaamazepin~~
.Cyclophos- Aldophosphamide, commonly used drug s including
y margin drugs , as well as
phamide phosphoramide mustard, wa1farin which are narrow safet
, celecoxib ~ ~J9sart,an .
acrolein ibuprofen, tolb_utami~ ~•- repaglinrde
ently used drugs including
Fluorouracil Fluorouridine CYP2Cl9 Metabolizes> 12 frequ
monophosphate ytoin , diazepam, propranolol.
omeprazole, lansoprazole, phen
potent inducers of the
Mercaptopurine MethylmercaptQpurine Rifampicin and carbamazepine are
e, is an inhibitor.
ribom,1cleotide CY!,~~ -~~bfamily, wfwe omeprazol
Acyclovir triphosphate participates in the meta -
Acyclovir CYPlAl/2 Though this subfamily
hylline, caffeine, paraceta-
bolism of only few drugs like theop
vert to more stable important for ~ f
mol, carbamazepine, it is more
intermediates which then con picin and carbamazepine,
procarcinogens. Apart from rifam
compounds . · polycyclic hydrocarbons, cigarett.
e smoke and charbroiled meat
carried out by
Oxidative reactions are mostly are ~ potent in~ucers.
in the liver, which
a group of ~onooxygenases CYP2El It catalyses oxidation
of alcohol, holothane , and
~ytochrorne P-450 of few drugs , notably the
in the final · step involve a formation of ~ e ~ s
chrome ~ oneimine from paracetamol;
hae mop rote in, NADPH, cyto hepatotox ic N-ac etyl benzoquin
.·
• I'vlorc than l 00 'chrome alcohoTisrnini:luces this isoenzyme
reducta~ and molecular 0 2 ·Tfierelafiveaii;~unt of different cytoc
hrome P-450s differ s
differing in their iduals of the same species.
cyt och ro~ e P-450 isoenzymes among species and among indiv
(dru gs), bave be.en for the mark ed interspecies
affinity for vaiious substrate s Thes e differences largely account
rate of metabolism of drugs .
and inte1individual differences in
identified.
imipramine,
Depending upon the extent of amin
o acid srquer,ce homology, Barbiturates, phenothiazines,
isoenzyme~. a,e gro uped into mol, steroids,
the cytochrome P-450 (CYP) propranolol, ibuprofen, paraceta
rals (1, 2, 3..... ), each having phylline and
families designated by nume phenytoin, benzodiazepines, theo
by capital letters (A, B, C. .... ), in this way. Few
several sub-families designated many other drugs are oxidized
again alloted numerals (1 , 2,
while individual isoenzymes are e, clozapine are
members of three isoenzyme drugs like cimetidine, ranitidin
3.... ). In human beings, only a few s by a group
families (CYP 1, 2 and 3) carry
out metabolism of most of the oxidized at their N, P or S atom
as tolbutamide, barbiturates, are also located
drugs, and many drugs such of flavin-monooxygenases that
than one isoform. The CYP , but are distinct
nifedipine are substrates for more at hepatic endoplasmic reticufum
are: '" ·· susceptible to
isoenzymes important in man from CYP enzymes. They are not
rmation of largest number r drugs, and thus
CYP3A4/5 Carryout biotransfo induction or inhibition by othe
ion to liver, these isoforms are ns. Some other
(nearly' 50%) of drugs. In addit
le (QI....firsL1:1ass metabolism are not involved in drug interactio
expressed ii} intestin~ (responsib n~e
-s well. Inhibition of this isoen
zyme drugs, e.g. ae9xe_n_aline, alcohol,
at t~j~~ ite) and ~ or cytoplasmic
by ery t~c in, c!arithrof!!Y.ci
n, ketoconazole, itraconazole are oxidized by mitochondrial
rtant drug interaction with
is responsible for the impo enzymes.
ride (seep . 166) which are
terfenadine, astemizole and cisap the converse of
its substrates. Losartan, nifedipine
hydrocortisone, mifepris- (ii) Reduction This reaction is
P-450 enzymes
tone, simvastatin, ritonavir, carba
mazepine and cyclosporine oxidation and involves cytochrome
3A4/5. Verapamil, diltiazem, on. A_Icoh~~_l_~,
are also metabolized by CYP working ~ 9 ~ ~
riton avir and a constituent of
grape fruit juice are other
picin, barbiturates and other aldehydes, q~ _~oneL are __!ed
u~ j - Dru gs /,;4
important inhibitors , while rifam
-------
,/ •j
I
I
'·1

anticonvulsants are the important

inducers.
,_r-.·
/
 GENERAL PHARMACOLOGY
primarily reduced are ch]oralhydrate, chloramp-
henicol, halothane, warfarin.
(iii) Hydrolysis This is cleavage of drug mole-
cule by t~g up a molecule of water.
Ester + H O esterase Acid + Alcohol
2 zid, PAS, dapsone, hydralazine, clonazepam,
Similarly, amides and p o l y ~ are hydrolysed
by a11J.idases'-a~d pe.eill;~s. In addition, th~re
are epoxide hydrolases which detoxify epox1de
metabolites of some 'drugs generated by .C:YP
~~ygen~se_~ _Hydrolysis c)ccurs in liver, intestines,
plasm<! and other tissues. Examples of hydrolysed
drugs are choline este1's, procaine, lidocaine,
procainamide, aspirin; carbamazepine-epoxide,
pethidine, oxytocin.
(iv) Cyclization This ~s formation of ring struc-
ture from a straight chain compound, e.g. proguariil.
. . - - --
(v) Decyclization This is opening up of ring
structure of the cyclic drug molecule, e.g: barbi-
turates, phenytoin. This is generally a minor
'
path~
Synthetic reactions
These involve conjugation of the drug or its
phase I metabolite with an en~ogenous_substrate,
usually derived from c,arb(?hydrate or amino acid,
to form a 120Jarltighly ioniiecrorganic ada;vmich
. ---··· -------
is easiiy excreted in urine or bile. Conjugation
reactions have ·high energyfequirement.
(i) Qlucuronide conjugation This is the most
--
important synthetic reaction carriedout by a group
of UDP-glucuronosyl transferases (UGTs).
Compounds with a hydroxyl or ~ylic-.acid
group are easily conjugated with glucuronic acid
which is derived from glucose. Examples are~
ch~amphenic~l, aspirin~a~-~ !~~~azepam,
loraz~m,_morphine, metronidazole. Not only
drugs but endogenous substrates like bilirubin
st~roidal hormones and thyroxine -utilize thi~
pathway. Glucuronidation i'ncreasesihe molecular
~eight of the drug which favours its excretion
in bile. Drug glucuronides excreted in bile can
be hy~olysed by bacteria in the gut-the liberated
drug 1s reabsorbed and undergoes the same fate.
This enterohepatic cycling (see Fig. 3.2). of the
drug prolongs its action, e.g. phenolphthalem, oral
contraceptives.
(ii) Acetylation Compounds havin~ amino or
hydrazine residues are conjugated w_i th th_e h~lp
~ m e - A , e.g. sulfonamides, 1sonrn-
procainamide. Multiple genes control the N-acetyl
transferases (NATs~ and rate of acetylati?~ _s~?ws
genetic polymorphism (slow and fast acetylators).
(iii) ~ he amines and phenols can
be methylated by methyl transferases (MT);
methionine and cysteine acting as methyl donors,
e.g. adrenaline, histamine, n i ~
methyldopa, captopril, mercaptopurme.
( i ~ e c~tion The phenolic com-
pounds and steroids are sulfated by sulfotrans-
:furases (SULTs), e.g. chloramphenicol, methyl-
dopa, adrenal and sex steroids.
(v) GJ_J(_cme_.conjuga-tieR-§alicylates, nicotinic
acid and other drugs having carboxylic acid group
are conjugated with glycine-2.,but this is not a major
pathway of metabolism.
(vi) Glutathione conjugation This is carried
~ - -- ---- ~
out b)' glutall110ne-S-transferase (GST) forming
a mercarililrate. It is normally a minor pathway.
How ever, it serves to inactivate highly reactive
quirn:me or epoxide intermediates formed during
metabolisrrtof~~tain drugs, e.g. paracetamol.
\.-Vhen large amount of such intermediates are
formed (in poisoning or after enzyme induction),
glutathione supply falls short-toxic adducts are
formed with tissue constituents ➔ tissue damage.
(vii) Ribonucleosidelift!_cleotide synthesis
This pathway is important for the activation of
many purine and pyrimidine antimetabolites used
in cancer cfiemotherapy.
Most drugs are metab;lized by many path-
ways, simultaneously or sequentially as illustrated
in Fig. 3.1. Rates of reaction by different pathways
often vary considerably. A variety of metabolities
(some more, some less) of a drug may be
produced. Stereoisomers of a drug may be
metabolized differently and at different rates, e.g.
 METABOLISM AND EXCRETION OF DRUGS, KINETICS OF ELIMINATION
el~
IL________ Ph~se II / Me;;;!!
~
Fig. 3.1: Simultaneous and/or se1quential metabolism
of a drug by phase I and phase 11 reactions
S-warlarin rapidly undergoes ring oxidation, while
R-warfarin is slowly degraded by sidechain
reauction.
--=---=---'
Only a few drugs are metabolized by enzymes
of intermedia ry metabolism, e.g. alcohol by dehy-
dro genase, allopurino l by xanthine oxidase,
succinylcn oline anaprocain e by plasma chol~- , the major causes · of individual variation in drug
terase, adrenaline by mom;Jarajne oxidase. Majority
of drugs are acted on by relatively nonspecific
. Hofmann elimination This refers to _inactiva-
enzymes which are directed to types of molecules
rather than to specific drugs. The same enzyme can
metabolize many drugs . The drug metabo1i sing
enzymes are divided into two types:
Microsomal enzymes These are located on
smooth endoplasm ic reticulum (a sy stern of
nrtcrotubul es inside the cell), primarily in li ver,
also in kidney, intestinal mucosa and iungs. The
monooxyg enases, cytochrom e P450, UGTs,
epoxide hydrolases, etc. an~microsoII1..aLenzy.r.nes.
They catalyse most of the oxidations_,__re_d.u.c-
tions, hydrolysis and gJ_!!furonide conjugation .
Microsomal enzymes-are inauctmeoy drugs, dfet
and other agencies.
Nonmicrosomal enzymes These are present
in th~ and mitochondria of hepatic cells
as well as-in othenissu esincluding plasma. The
esterases, amidases, some flavoprotein oxidases
and most conjugase s are nonmicros omal.
Reactions catalysed are:
Some oxidations and reductions, many hydro-
lytic reactions and all conjugatio ns except
glucuronidation.
The nonmicrosomal enzymes are not inducible but
many show genetic polymorphism (acetyl trans-
ferase, pseudocholinesterase ).
Both microsomal and nonmicrosomal enzy-
mes are deficient in the newborn, especially
premature, making them more susceptible to many
drugs, e.g. chloramphenicol, opioids. This deficit
is made up in the hrst few months, more quickly
in case of oxidation and other phase I reactions
than in case of glucuronide and .other conjugations
which take 3 or more months.
The am"'ount and kmd oC'drug meta~olizing
enzymes is controlled genetically and is also
altered by ~ Thus, marked
interspecies and interindividual differences are
seen, e.g. cats are deficient in UGTs while dogs
are deficient in NATs. Upto 6-fold difference in
the rate of metabolism ·of a drug among normal
human adults may be observed. This is one of
response.
tion of the drug in tl}e boQY_f1uids by__ spon~ou s
moie~~~-a~ without the agency of
any e ~ e..g.~~ -
1
}.(i1 A'.BrnoN OF DRUG METAB_OLISM
One drug can competitively inhibit the metabolism
of_ another if it utilizes the same enzyme or
cofactors. However, such interactions are not as
common as one would e_x ~ct, because often
differefitdrugs are substrates for different
CY P-450 isoenzymes. It is thus important to
know the CYP isoenzyme(s) that carry out the
metabolism of a particular drug. A drug may inhibit
one isoenzyme while being itself a substrate of
another isoenzyme, e.g. quinidine is metabolized
mainly by CYP3A4 but inhibits CYP2D6. Also
most drugs, at therapeutic cqncentrations, are
metabolized by Cnon-saturation. kinetics, i.e. the
enzyme is present in excess. Clinically significant
infiTIJftion of drug metabolism occur,s in case of
drugs having affinity for the same isoenzyme,
specialtyT fllieyare metabolized by satl!ration
kinetics or if kinetics changes from first order
 ·F
\
GENERAL PHAR MACO LOGY ~;=-=J
;...~~~~ ~ -
D
Drugs that inhibit drug metab olizing enzym
es
• Isoniazid and chronic alcohol ~;um ption
induce CYP2 El.
r- -
Allopurinol Amiodarone Poly'cyc\ic hydrocarbons like 3-methykholan- \I ~~
ta
Omeprazole Propbxyphene threne· a n d ~e found in . dgare tt~
Erythromycin lsoniazid
Clarithromycin Cimetidine
smoke, charcoalbroilef ~ omeprazo1e and
Chlora·mphenicol Quinidine industrial pollutants induce ~:YP I A iso-
Ketoconazole Disulfiram enzymes.
ltraconazole \ :
Diltiazem
Metronidazole Verapamil
Other impo rtant enzym e induc ers are : \
Ciprofloxacin MAO inhibitors phenylbutazone, griseofulvin, DDT. \
Sulfon amides Ritonavir (and other
Fl~oxetine (and
Since differ ent CYP isoenz ymes are involv ed in
HIV protea se
other SSRls ) inhibit ors) the metabolism of different drugs , every inducer
\
increasesbiotransformation of certain drugs but
to zero order over the therapeutic range (capacity not that of others. However, phenobarbitone like
limited metabolism). Obviously, inhibition of drug inducers of C~P_:1_~3nd CYP2D6 affect the
\
metabolism occurs in a dose related manner and metabolism of a large number of drugs,, becau se \
can precipitate toxicity of the object drug (whose these isoenzymes act on many drugs. On lhe other
\
metabolism has been inhibited). hand induc tion by polyc yclic hydro carbo ns is
Because enzyme inhibition occurs by direct limited to few drugs (like theophylline, ph~na-
'
effect on the enzyme, it has a fast time course cetin) because CYP lA isoenzyme metabolizes
(within hours) compared to enzyme induction (see only few drugs.
below). Induction involves microsomal enzymes in
Meta bolis m of drugs with high hepat ic liver as well as other organs and increases the
'
extraction is depen dent on liver blood rate of metabolism by 2-4 fold. Induction takes
flow c:-- -
(blood flow limited metabolism). Propr ano1g 4--14 days to reach its peak and is maintained
J
reduces rate of lidocaine metabolism by decreasing; tin Hie inducmg agent is being given. Thereafter
hepatic blood flow. Some other drugs whose rate z.hc t\ffl ymes return to their original value over
of metabolism is limited by hepatic blood flmv :i--3 weeks.
are morphine, ·propranolol, verapamil and imi2ra-
. ~~
f'.:C\)\nS;;siquen ces of microsomal
mme.
.,,--- :0rtl?f une 1nduction
MICROSOMAL ENZVME INDUCTION 1. Decreased intensity and/or duration of action
of drugs that are inacti vated by metab olism
Many drugs, insecticides and carcinogens interact ,
e.g. failure of contraception with oral contra
with DNA_ and incre ase .the synth esis of -
ceptives.
microsomal enzyme protein: especially cytoch- 2. Increased intensity of action of drngs that are
rome P-450 and UGTs As a result rate of meta- activated by metabolism. Acute paracetamol toxi-
bolism of inducing drug itself and/or other drugs city is due to one of its meta
is increased. bolite s-tox icity
occurs at lower doses in patients receiving enzym
e
Different inducers are relatively selective for inducers.
certain cytochn_)me P-450 isoenzyme families, e.g.: 3. Tole ranc e-if the drug induc es its own
• Anticonvulsants (phenobarbitone, phenytoin, metabolism (autoinduction), e.g. carbamazepine,
carba maze pine ), rifam pin, gluco cortic oids rifampin.
induce £YB A-ise enzy mes. 4. Some endog enous substrates (steroids, bili-
• Pheno barbi tone also induces CYP2 B l and rubin) are also metab olized faster.
-----~-- -
rifampin also induces- CYP2 -0o._ _ ___
\

5. Precipitation of acute intermittent. porphyria:

enzym e induction increases porphyrin synthesis
'\
c... ~'.~ -
 ~,;.
~
~ -~
:, META BOLIS M AND EXCRETION OF DRUG
S, KINETICS OF ELIMI NATIO N
by derepressing o-aminolevulenic acid synthe
- in th~ gut <!nd liver can be avoided by adminis-
tase. tering the drug through sublingual, transdermal
6. Intermittent use of an inducer may interfe
re or parenteral routes . Howe '~iimited presystemic
y
with adjust ment of dose of anothe r drug pres- niefaoolism can occur in the skin (transdermall
ng
cribed on regula r basis, e.g. oral anticoagulan
ts, administered drug) and in lungs (for drug reachi
of
oral hypoglycaemics, antiepileptics, antihyperten
- venous blood through any route). The extent
sives. first pass metabolism differs for different drugs
of
7. Interf erence with chronic toxicity testing
in (Table 3.1) and is an impor tant determinant
animals. oral bioavailability.
Drugs whose metab olism is signif icantl y Attributes of drugs with high first pass
affected by enzym e induc tion are-p henyt oin, metabolism:
warfarin, tolbut amide , imipramine, oral contra
- (a) Oral dose is considerably higher than sub-
ceptiv es, chlora mphe nicol, doxyc ycline , theo- lingu-a rorparentera1 dose.
phylline, griseo fulvin , phenylbutazone. (b) There is marked · individual variation in the
oral dose due to differences in the extent of first
Possible uses of enzyme induction pass metabolism.
in
(c) Oral bioavailability is apparently increased
1. Conge nital nonhaemolytig__jaundice: It is due
- patients with severe liver clisease.
to defici ent glucu ronida tion ofnili rufon ; pheno if
(d) Oral bioavailability of a drug is increased
barbi toneh asten s cleara nce of jaund ice.
anoth er drug comp eting with it in first pass
2. Cushi ng's syndro me: pheny toin may reduce ro-
of metabolism is given concurrently, e.g. chlorp
the manif estatio ns by enhan cing degradation
. mazine and propranolol. .
adrenal steroi ds which are produ ced in excess
of
3. Chron ic poison ings: by faster metab olism EXCR ETIO N
the accum ulated poison ous substance. Excre tion is the passag e out of systemically
4. Liver diseas e. phsorbed drug. Drugs and their metabolites
are
excre ted in :
FIRS T PASS (PRE SYS TEM!CJ
~Jr~nf.) Through the kidney. It is the most
META BOLI SM of
importani channel of excret ion for major ity
its
This refers to metab olism of a drug during drugs (see below).
sys-
passag e from the site of absorp tion into the
2. Faeces Apart from the unabs orbed frac-
temic circul ation. AU ora11y admin istered drugs d
the tion, most of the drug presen t in faeces is derive
are expos ed to drug metab olizin g enzym es in
from bile. Liver actively transp orts into bile orga-
intestinal wall and liver (wher e they first reach
nic acids (especiaIIy drug glucu ronide s by OATP
through the portal vein). Presy stemic metab olism
{ll):1f§'{jJtJ Extent of first pass metabolism of some
important drugs
Intermediate ----,- --,--- -,,--- H_i~ g_h_ ~~-- ----
Low not given orally high oral dose
lsoprenaline Propranolol
Phenobarbitone Aspirin
Lidocaine Alprenolol
Phenylbutazone Quinidine
Hydrocortisone Verapamil
Tolbutamide Desipramine
Testosterone Salbutamol
Theophylline Nortriptyline
Glyceryl trinitrate
'•{_ Pindolo_ l \ Chlorpromazine
Morphine
-\ lsosorb1de \ Pentazocine
Pethidine
mononitrate \ Metoprolol
 ~
1
rl
GENERAL PHARMACOLOGY
and MRP 2) , organic bases (by OCT), 3. Exhaled air Gases and volatile
other liquids
lipophilic drugs (by :P-gp) and steroids by (general anaesthetic s, alcoh
distinct ol) are elimi nated by ,
nonspecific activ e trans port mech anism lungs, irrespective of their lipid solubility. Alveo
s. lar
Relatively larger molecules (MW > 300) transfer of the gas/v
are apou r depen ds on its partial
prefe rentially eliminated in the bile. Most pressure in the blood
of the . Lung s also serve to trap and
free drug in the gut1 including that relea extrude any particulate matter that
sed by enters
deconjugation of glucuronides by enteric circulation.
bacteria
is reabsorbed (ente rohepatic cycling) and ultim ate
excretion occurs in urine (Fig. 4. Saliva and sweat Thes e are
3.2). Only the of mino r
remaining is excreted in the faeces. Enter importance for drug excretion. Lithi um
ohep atic , pot.
cycling contributes to longer stay of the iodide, rifam pin and heavy metal s are prese
drug in nt in
the body. Drugs that attain high conc entra these secretions in significant amounts.
tions Most of
in bile are erythromycin, ampicillin , rifam the saliva along with the drug in
pin, it, is swallowed
tetracycline, oral contraceptives, vecu and meets the same fate as orally taken
ronium, drug.
phenolphthalei n.
Certain drugs are excreted 5. Milk The excretion of drug in milk
direc tly in colon, is not
e.g. anthracene purgatives, heavy meta impo rtant for the moth er, but the suckling
ls. infant
inadvertently receives the drug. Most drngs
enter
,
Systemic
/
lg
-0 ENTEROHEPATIC -~
>
(J) CYCLING OF DRUGS
~-- IP ~ ~
tf
;,;;~~\
~
\ l
\\ -\
Bacterial
\ ·.ti \:"' deconiuqases
Uri
Faeces
Fig. 3.2: Enterohepatic cycling of drugs
In the liver many drgus (D), including
steroids, are conju gated by the enzym
transferases (UGTs) to form drug-glucu e UDP-glucuronosyl
ronide (DG). Part of the DG enters
and is excreted into urine by the kidne systemic circulation
y through both glomerular filtration
tubular secretion involv (GF) as well as active
ing renal organ ic-ani on transp orting peptide (OATP).
Another part of DG is actively secre
ted into bile by the hepat ic OATP .
lumen via bile, a major part of DG is On reaching the gut
deconjugate d by becte rial hydro lytic
while the remaining is excreted into enzym es (deconjugases)
faece s. The releas ed D is reabs orbed
reach the liver through portal circula from the gut to again
tion and complete the enterohepatic
cycle .
 METABOLISM AND EXCRETION OF DRUGS, KINETICS OF ELIMINATION
1uids
breast milk by passive diffusion. As such, more
d by Glomerular filtration q1omerular capillaries
lipid soluble and less protein bound drugs cross
~olar have pores larger than usual; all nonprotein hound
better. Milk has a lower pH (7.0) than plasma,
utiaJ drug (whether lipid-soluble or insoluble) presented
basic drugs aresoinewhat more concentrated in
and to the glomerulus is filtered. Thus, glomerula;
it. However, the total amount of drug reaching
1ters filtration of a drug depends on its plasma
the infant through breast feeding is generally small
binding and renal blood flow. Glomeru1ar'
and majority of dmgs can b_e given to lactating
mothers without ill effects on the infant. Never- rate (g.f.r.), normall y ~ 120 ml/min declines pro-
nor
gressively after the age of 50,· and is low in renal
JOt. theleis~1tTsaclvisable to administ~· any drug to
failure. ~ --
: in a lactating ·woman only when essential. Drugs
of that are safe, as well as· those contraindicated Tubular reabsorption This occurs by passive
ed
1 during breast feeding or need special caution are diffus10n and depends on lipid solubility and
1g. given in Appendix-4 at the end of the book. ionization of the drug at the existing urinary pH.
Lipid-soluble drugsfiltered a!ltie glomerulus back:
1ot RENAL EXCRETION! diffuse m the tubules because ~
nt
fil'ffiife1srea~ but nonlipid-soluble and
er The kidney is responsible for excreting all water
mghly ionized drugs are unable to do so. Thus,
soluble substances. The amount of drug or its
metabolites ultimately present in urine is the Sl!Iij rateofexcretwn 6Csuch dru~ s, e.g. aminogly-
cos'ioe antibiotics, quaternary ammonium
total of glomeiular filtration, tubular reabsomtion
compounds parallels g.f .r. (or creatrnine
and tubular secretioo. (Fig. 3.3).
clearance). Changes in urinary pH affect tubular
----
Net renal (Glomeruli " filtration + tubular
' - tubular reabsorption
excretion -- secretion)
reabsorption of drugs that are partially ionized-
• --W-eak bases ionize more and are less reabsor-
f
bed in acidic urim;.
~ " Weclk acids ionize more and are less reabsor-
Afferent ~~ ~~ "T--
Z·"' ,
Efferem ,
arteriole
G~J~~~, . \\ arteriole
be~ n a1ka~ 11rine.
~~~\ , \ \~-:~_-·,
This principle is utilized for facil_itating elimina-
f ·~,\\\ Li tiSn of the drug in poisoning, i.e. urine is alkali-
. I lU
7 Fl
nized m basbiturate and salicylate poisoning.
Plasma ~ ,:f
I
I
/J''. .IJ Though elimination of w~rp-hirre;-
protein f arnphetam~ n be enhanced by acidifying
mine, this is not practiced clinically, because
L
u
acidosis can induce rhabdomyolysis, cardiotoxi-
Peritubular
Tubular m vessel city and actually worsen outcome. The effect of
cell .. ch~nges in urinary pH on drug excretion is greatest
:r · fo1- those having pKa values between 5 to 8,
Urinary
pH
because only in their case pH dependent passive
reabsorption is significant.
~ Thi~ r
of~ basesbytw~
of relatively nol!fil)ecifictransporters (05[._.and
Fig. 3.3: Schematic depiction of glomerular filtration, OCT) which operate in the prox imal tubules. In
tubular reabsorption and tubular secretion of drugs
FD-free drug; BO-bound drug; UO-unionized drug;
addition, 'ci1-lux transporters P-gp and MRP2 are
ID-ionized drug; Ox-actively secreted organic acid (or located in the luminal membrane of proximal
base) drug ·( tubular cells. If renal clearance of a drug is greater
...
's, •
..... ,.(''
,~. '.,..._
...
__
· .\._ ::..
 GENERAL pHARMACOLOGY
.
(iv ) Quinidine .decreases
'b' .
renal and bi Ii
tubular di aoxin by mh1 itmg effl ux carrie ary cl
p earan
dditional of i:, r -gp ce
• (g f.r.), a rrin 11 • Tubular transport mechanisms a ·
I 20 111Lf1111n .d to be occu ; tubules re
than be assume drug acros tubU- developed at birth. As a result, duratio not well
etiot) can of the in the . . 'l . n Of
f
seerActive transpo_1t of its free 9~_111_ of protetn of many drugs,_ e.g. pemc1 Im, cephalos ac~ion
11
. duces concen tratJ01-oies-<d1sso ciat10n
. vailable io c r
Sp irin is longer m neonates.. These systerns Por1n8'
1e d pron mes a •h a during infancy. Renal function again pr lllature
Jar vessels an i..; h then beco . b'n.ding, whic
wwc ... . tel0 J ogress·
bound_ diug: . 3,3). Thus, pro filtration of the declines after the age of 50 years; renal 1
Vely
1
secret10n (fig. for gJomerular t cilitatory) to of most drugs is substantially lower in t:ee~rance
. a hinderance even be a ..
is . . so (may
drug, _1s nt tubular secret10n.
. ~TI~- ¾
OATP)
excretmn Y t (through .
. . . acid transpor .d uric acid, KINETICS OF ELIMINATION
(a) Organic . . . robeneci ' . -
. . . for pemc1llm, p If' yratorte, mtro The knowledge of kinetics of eliminat·
operates h cin, su mp . d drucr provides the basis . ion of
salicylates, indomet a druu ulucuromdes an for, as wen as a
. methotrexate, o o i:, • serves
furantom, to devise rational dosage regimens and to rn d'
sulfates, etc. _ (throuuh o·CT) them according to individual needs. Ther: ~fy
. . . base transport b three fundamental pharmacokinetic pararnete e
(b) Or,gamc__ .
·· · · . ·azides arm.1Ori'de ' triamterene,
• viz. bi?a;.'.ailability (F), ~olu~e of distribution(~
Operates for thi• · ' . arm'de, choline,
furosemide, qumme, procam a n d ~ which must be understood.
cimetidine, etc. rt processes are bi- The first two have already been considered.
Inherently both tran_spo rt their substrates Drug elimination is the ~umtotal of metabolic
. al · they can transpo ~
inac~ivation and excretion'. As depicted in ~
direct10n ' 1.e. fluidand vice versa. How-
from ~roddru~gs~~~;eir 2.1, drug is eliminated only from the central
m
meettaabboo~
. s I(exogenous
ever tor ctru~ •. ;b~1 I men compartment (blood) which is in equilibrium with
sub~tances) secretion _int_o the tu u a~ u
predo~s, whereas an _endogenous substrate peripheral compartments including the site of
like ;ric acid is predominantly reabsorbed. action. Depending upon the ability of the body
Drugs utilizing the same active transport co~- to eliminate a drug, a certain fraction of the central
pete with each other. Pro?~~~cid is an orgamc compartment may be considered to be totally
acid _which has high affmity for the tubl!_lar OATP. 'cleared' of that drug in a given period of time
It blocks the acfive transport of both penicillin to account for elimination over that period.
and uric acid, but-whereas--the-net--e-XGretion-of
the former is decreased, that of the .latter is Clearance (CL) The clearance of a drug is
increased. This is because penicillin is primarily the theoretical volume of plasma from which the
secreted ~!:ill~-~ is ptimarilfreabsorbed. drug·is completely removed m unit tim~(analogy
Many drug int~a~tion~_c~~ciircfiietocompefftion creatirune clearance; Fig. 3.4). It can be calculated
~
for tubaj_~ _i~e!jon, e.g:- ·- · ----- as
(i) Sali~yla_ te~ block uricosuric action of probene- ...(!)
CL= Rate of elirnination/C
cid and---s-uJfiup_yB!~ne_iina_ciecreasetwfo-tar
secretion of methotrexate. where C is the plasma concentration.
(ii) Probenecid decreases the concentration of For majority of drugs the processes involved
nitr_ofurantoin in urine, increases the·duration of . e1·urunat10n
m · · are not saturated over the c1·mic· ·ally
act10~ of penicillin/ampicillin and impairs obtained concentrations, they follow:
secretion of methotrexate.
(ii_i) Sulfinpyrazone inhibits excretion of tolb . - First order kinetics The r a t e ~
m1de. uta d1.~1 roportional to
- --
the drug concen
rrauon. _
. f
CL remai~· stant; or a constant ctwtO~ 0
- Jtraau
~ fl
- --- -----·
s-,~---..
 - -•---•vr /-\l~U tXLRETION OF DRUGS, KINETICS OF ELIMINATION
~
elimination, and is given i.v. a semilog plasma
concentration-time plot as shown in Fig. 3.5 is
obtained. The plot has two slopes.
initial rapidly declining (a) phase-due to
distribution.
later less declined (~) phase-due to elimina-
tion.
= 50 ml/min At least two half-lives (distribution t½ and
elimination t½) can be calculated from the two
slopes. The elimination half life derived from the
Fig. 3.4: Illustration of the concept of drug clearance. A ~ sl?P~ _i_s simply called the 'half life' of the drug.
traction of the drug molecules present in plasma are
removed on each passage through the organs of Most · drugs infact have multicompartment distribution and
elimination. In the case shown, it requires 50 ml of plasma multiexponential decay of plasma concentration-time plot.
to account for the amount of drug being eliminated every Half-lives calculated from the terminal slopes (when plasma
minute: clearance is 50 mUmin concentrations are very low) are exceptionally long, probably
due to release of the drug from slow equilibrating tissues,
enterohepatic circulation, etc. Only the t½ calculated over the
the drug present in the body is eliminated . . steady-state plasma concerttration range is clinically relevant.
. Th" moort It is this tY2 which is commonly mentioned.
time. is applies to majority of drugs .which
do not saturate the elimination processes (trans- Mathematically, elimination t½ is
porters, enzymes, blood flow, etc.) over the
ln2
therapeutic concentration range. However if t½ = - - ... (2)
the dose is hig_h enough, elimination pathw,ays k
of all drugs will get saturated. Where ln2 is the natural logarithm of 2 (or 0.693)
.Few drugs normally saturate e)_i1ru natin!Y rnec- 0
and k is the elimination rate constant of the drug,
hamsms and are handled by-•-- i.e. the fraction of the total amount of drug in
the body which is removed per unit time. For
Zero order kinetics The ,·~i:::' :.: / elimination
remains constant irre.Sf-.xtiv;i: cf conccu-
tration, CL decreases \ Vi ih ,z,::n:1se in conccn-- r"
tration; or a constan t mnount of the drug is
eliminated in unit time, e .g. ethyl alcohol. This
is also called capacity liniited elimination or
I
~·~ 16
'".'ai'
Michaelis-Mente n elimination.. Oro
·Z u 8
The elimination of some drugs approaches 0~
saturation over the therapeutic range, kinetics
O Ol I I 1
<( ~ 4f---r--., .--
changes from first order to zero order at higher ~ '--'
doses. As a result plasma concentration increases ~
..J
2f---L __ .1 __ J __
I I I
disproportionatel y with increase in dose (see Fig. 0. I I
3.6), as occurs in case of phenytoin, tolbutamide, ,-t½-1
theophylline, warfarin . I I
Plasma half-life The Plasma half-life (t½) of 2 4 6 8 10
a drug is the time taken for its plasma concen- T ime (Hours) .
tration to be reduced to half of its original ~e. Fig. 3.5: Semilog plasma concentration-time plot of a
Taking the simplest case of a drug which has drug eliminated by first order kinetics after intravenous
rapid one compartment distribution and first order injection
 :h
}'
., i' il
• f
I:
;i
,i i 32 GENERAL PHARMACOLOGY

of the drug has been worke d out and its CL .

example, if 2 g of the drng is present in the body known, the dose rat~ needed to achieve the targ::
and 0.1 g is eliminated every hour, then
Cpss can be de term Ined-
k = 0.112 = 0.05 or 5% per hour. ... (6)
dose rate == target Cpss x CL
It is calculated as:
z . a fractio n
After oral administration, often . only
0 CL
;::: - -
k - ... (3) (F) of the dose reache s system ic circula tion in
0 v the active form. In such a case -
w V
en therefore t½ = 0.693 x - - ... (4) target Cpss x CL
CL ... (7)
dose rate = F
As such, half-life is a derived parameter from
two variables V and CL both of which may change The dose rate-Cpss relationshi_P is linear only in
independently. It, therefore, is not an exact index case of drugs elimin ated by first order kinetic
of dmg elimination. Ne,yertheless, it is a simple For drugs (e.g. pheny toin) ~hich follow Micha eJ~
and useful guide to the sojourn of the drug in Mente n kinetic s, eliminat10n chang es from first
the body, i.e. after order to zero order kineti cs over the therapeutic
l t½-50 % drug is eliminated. range. Increa se in their dose beyon d saturation
2 t½-75 % (50 + 25) drug is eliminated. levels causes an increa se in ~pss which is out
3 t½- 87.5% (50 +'25+ 12.5) drug is eliminated. of propo rtion to the chang e m dose rate (Fi g.
4 t½-93.75% (50 + 25 + 12.5 + 6.25) drug
3.6). In their case:
is eliminated.
(V,nax) ( C)
Thus, nearly complete drug elimination occurs in = -K- - -
Rate of drug
- elimin ation ... (8)
4-5 half lives. m + C
For drugs eliminated by-
First order kineti cs-t½ remains constant because where C is the plasm a conce ntratio n of the druo
V,,1ax is the maxim um rate of drug eliminati on,
i:, ,
V and Cl do not change with dose. . h
an.d .K111 .1s t e plasm a conce ntrati on at wh· h
Zero order kineti cs-t½ increa ses with dose IC
because CL, progressively decreases as dose is _e I1mmat10n rate is half maxim al.
increased. ·

Halt lite of some representative drugs

Aspirin 4 hr Digoxin . 40 hr
Penicillin-G 30 min Digitoxin 7 days
Doxycycline 20 hr Phenobarbitone 90 hr

Repeated drug administration

Cl)
Cl)
. a..
u
Whe~ a drug is repeated at relatively short inter- (l)
. .
vals, it accumulates in the body until el·1mmat 0)

bala · 10n ~
trati:e(sCmp)ut_and ~ s_teady state plasm a concen- (l)
>
pss 1s attam ed- <{

dose rate
Cpss =
CL
From this equation it is im .
dose rate would d bJ phed that doubling the
ou e the averag e Cpss and so
.
on. Further' if the th erapeut1c
pJasma concentration
... (5)
. Dose. r te - , •
b - ·
Fig. 3.6: Relationsh·
steady-state pl 'P etween dose rate and average
by first order an~s~~ con~entration of drugs eliminated
rchaells Menten (zero order) kinetics

,,·
I
 METABOLISM AND EXCRETION OF DRUGS, KINETICS OF ELIMINATION

Plateau principle some time), average Cpss is approximately 1./3

When constant dose of a drug is repeated before
the expiry of 4 t½, it would achieve higher peak
conce·ntfation, because some remnant of the
previous dos~ will be present i~ the body.. This
continues with every dose until progressively
increasing rate of elimination (which increases
with increase in concentration) balances the
amount administered over the dose interval.
Subsequently plasma concentration plateaus and
fluctuates about an average steady-state level. This
is known as the plateau principle of drug accu-
mulation. Steady-state is reached in 4-5 half lives
unless dose interval is very much longer than
t½ (Fig. 3.7).
The amplitude of fluctuations in plasma
concentration at steady-state depends on the dose
interval relative to the t½, i.e. the difference
between the maximum and minimum levels is
less if smaller doses are repeated more frequently
(dose rate remaining constant). Dose intervals are
gene-rally a compromise between what amplitude
of fluctuations is clinically tolerated (loss of
efficacy at troughs and side effects at peaks) and
what frequency of dosing is conve1uent. Hmvever,
if the dose rate is changed, a new ;:ivr;::rB._g,;;: L-'pss
is attained over the next 4--5 half l).'-' ?:~. \Vben
the drug is administered oraliy (tbs-::,cption takts
r-=:------....,,...--:-- ...---:7"""":.o. ._,~ . ·~·. :· ·:.._~~~ {. ·_::-.·::.,, ·c'..;,(j
C
- - • Maximum
0
; erage
·e,.s
'ECl)
0 F
C:
8 1
a,
E by CL or t½.
(/)
~ 0.5
0.
2 3 4 5
Time (multiples oft½)
Fig. 3.7: Plateau principle of drug accumulation on
repeated oral dosing.
Note. The area of the two shaded portions is equal
of the way between the minimal and maximal
levels in a dose interval.
Target level strategy For drugs whose effects
are not easily quantifiable and safety margin is
not big, e.g. anticonvulsants, antidepressant~,
lithium, antiarrhythmics, theophylline, some anti-
microbials, etc. or those given to prevent an event,
it is best to aim at achieving a certain plasma
concentration which has been defined to be in
the therapeutic range; such data are now available
for most drugs of this type.
Drugs with short t½ (upto 2-3 hr) adminis-
tered at conventional intervals (6-12 hr) achieve
the target levels only intermittently and fluctua-
tions in plasma concentration are marked. In case
of many drugs (penicillin, ampicillin, chloramp-
henicol, erythromycin, propranolol) this however
is therapeutically acceptable. .
For drugs with longer t½ a dose that 1s
sufficient to attain the target concentration after
single administration, if repeated will accum~l~te
according to plateau principle and produce toxicity
later on. On the other hand, if the dosing is such
BS to attain target level at steady state, the
therapeutic effect will be delayed by about 4 half
lives (this may be clinically unacceptable). Such
drugs are often administered by initial loading
and subsequent maintenance doses.
)
·.1 Loading dose This is a single or few quickly
:,l repeated doses given in the beginning to attain target
concentration rapidly. It may be calculated as-
.'-- target Cp x V
nimum
Loading dose = ... (9)
Thus,loading dose is governed only by V and not
Maintenance dose This dose is one that is to
be repeated at specified intervals after the
attainment of target Cpss so as to maintain the same
6
by balancing elimination. The maint~nance dose
rate is computed by equation (7) and_ is.~~verned
b CL (or tY2) of the drug. If fac1ht1es for
i:easurement of drug concentration are available,
 GENERAL PHARMACO
LOGY

attainment of target level 6. To ch ec k pa tie nt co

in a p~tient c~n be v~ti~ed mp lia nc e
subsequently and dose rat
e adJus~ed if re~mre :a- ph arm ac olo gic al agen
Such two phase dosing ts. ' e.g. --p~Y1:h<:i,
provides rapid thei ,_
peutic effect with long Sel ect ion of the cor rec
t interval between d
teim s~fety; freque~tly
z ap pli ed to digoxin, ch
lor oq um ~, lo ng -a ctm
and dra wi ng of blo od sam
ple for TD M is c ~~g actn
0 g on the pu rpo se of ,inist .
as we ll as· th nttca\
.::
0
su lfo na mi de s, do xy cy
However, if there is no urg
cli ne , am10darone, etc
.
dru g
.
TD M
.
. rat
'and dep 111n
e nature enu ~
w ency, maintenance dose a. When the purpose Of th
can be oiven from the s is dose adjustment" l
en beginning. Th e co nc ep
t
.
w h 1c h nee d to act con .
tin uo usl y (relati . n case
e
of loadi~g and mainten · ·
drug s) , 1t d v of dru
ance dose is .vali_d_ als 1s pru ent to measure I
the troue hY Iong-acting,~
forshortt½drugs and i.v. o bl oo d 1eve1s, · · •
administration m cnt1call 1.e. Jus t pn or to the next d steac1 g
ill patients, e.g. µdocain y this i~ gov ern ed by bo Y·state&
e (t½ 1.5 hr) us ed fo th V and CL. On those,
r for short-acting dru gs because
cardiac arrhythmias is'•giv . wh ich achieve th e 0th
en as an i.v. bolus do se .
only intenruttently (e.g . . er hand
followed by slow i.v. . amp1cillin, gentamera ici
peuti I '
infusion or int erm itt en is do ne in the im me dia c evel s
fractional dosing. t te post-absorptive phn),
sampling
after 1-2 hou rs of ora
l/i.m. dosing) to refle:s
. i levels . ; ?sua\\y
Monitoring of plasm
I
: a concentration of b. In case of poison he Peak
drugs It is clear from the ing: Blo od for drug lev
above considerations sho uld be tak en at the · el .
that the Cpss of a drug ear hes t to confirm th esti.mati0
attained in a and to gau ge its ser iou n
given pa tie nt sne ss. It should then eb poison·
depends on its F, V and CL at int erv als to mo nit tng
in that patient. Be ca us e or the progress. e repea• cl
,e
each of these pa ram ete c. For checking com
rs va rie s co ns ide rab ly .
pli an ce to me dic ati on·
blo od sam pli ng can . Eve
among individuals, the be inf orm ati ve. · n random
actual Cpss in a patie
may be 1/3 to 3 times tha nt
t calculated on the basis Monitoring of plasma
of population data. Mea concentration is of no
surement of pla sm a dr value for
co nc en tra tio n ca n gi ug
ve an · es tim ate of th
pharmacokinetic variable e 1. Dr ug s wh os e re sp
s in th at patient and the on se is ea sil y measurab
magnitude of deviation e. g. - an tih yp er ten siv le
from the .'average pa tie es , hypoglycaemics'
so that appropriate ad nt' , diuretics, ora1 an tic oa
justments in the do sa gu lan ts, general anaes~
regimen can be made. ge thetics.
2. Dr ug s activ at-!:; -d. in
In case of drugs o~ ~i th e body, e.g .-l ev od op
ng first order kinetics 3. 'H it an d ru n d:ru.gs' a.
: (w ho se effect lasts much
Re vis ed = Pre vio us
-do se rat e x Ta rge t lo ng er th an th e drug
do se rat e Cpss itself), e.g .-r es erp ine ,
M eas ure d Cpss .. .(10) gu an eth idi ne , M AO inh
ibi tor s, omeprazole.
Th er a~ ut ic drug monitori 4. Dr ug s wi th irr ev ers
ng (TDM) is particularly ibl e ac tio n, e.g .-o rg an
ph os ph ate an tic ho lin es o-
useful m the following ter as es , phenoxybenza-
situations:
1. D~ gs with low safety mine.
margin, e.g. -d ig ox in ,
ant~convuls~ts, antiarrh
ythmics, theophylline,
ammoglycos1de antibiot PROLONGATION OF
ics, lithium, tricyclic DRUG ACTION
antidepressants.
It is so me tim es ad va nt
2. If individual varia ag eo us to modify a dru
tions are large, e. g. -a in su ch a wa y tha t it g
depressants, lithium. nt i- ac ts fo r a longer perio
By do ing so: d.
3. Po ten ti~ ly toxic dru
gs used in the presence (i) Fr eq ue nc y of ad mi
renal failure, e.g. -a mi no of nis tra tio n is re du ce d- mo
. gl yc os id e antibiof convenient. re
vancomycm. lCS,
4. In ca se of poisonin (ii) Im pr ov ed pa tie nt
g. co m pl ia nc e- a single
5. In case of failure mo rn ing dose is less lik
of response without ely to be forgotten/omitte
tha n a 6 or 8 ho ur ly d
apparent reason, e.g. -a re gi me n; a monthly
nt im icr ob ial s. any quarterly ad mi nis ter ed or
co ntr ac ep tiv e over one th
has to be tak en daily at
.
 METABOLISM AND EXCRETION OF DRUGS, KINETICS OF ELIMINATION

... Large fluctuations in plasma concentration in that time drug particles reach the colon. Also,
(ri~) avoided-side effects related to high peak
the drng release pattern and consequently the
a~<:sma level _.i~st _after a dose (e.g. nifedipine) attained blood levels of the drug may be more
P Id be m1m1111zed; better round-the-clock
wou variable than the regular tablet of the same drug.
l of blood sugar, etc.
contro . . (b) Parenteral . The s.c. and i.m. i_n~e~tion of
s
. ) o111t::>u effect
(IV . •
could be marntamed
•
overnight
druo in insoluble form '(benzathine pemcillm, lente
without disturbing sleep, e.g. antiasthmatics,
insclin) or as oily solution (depot progestins);
anticonvulsants, etc.
pellet implantation, sialistic and bio?egradable
However, al] drugs do not need to be made
implants can provide for its absorption over a
Jong acting, e.g. those used for brief therapeutic
couple of days to several months or even years.
effect (sleep-inducing hypnotic, headache remedy)
Inclusion of a vasoconstrictor with the drug also
or those with inherently long duration of action
delays absorption (adrenaline with local anaes-
(doxycycline, omeprazole, digoxin, amlodipine).
thetics).
Drugs with t½ .5. 4 hr are suitable for controlled
release formulations, while there is no need of (c) Transdermal drug delivery systems . The
drug impregnated in adhesive patches, ~tnps or
such formulations for drugs with t½ ~12 hr.
as ointment applied on skin is · utilized m some
Methods utilized for prolonging drug action are
cases to prolong drug action, e.g. GTN (see
summarised below. Some of these have already
been described. p. 8).
2. By increasing plasma protein binding
1. By prolonging absorption from site of
administration Drug congeners have been prepared which are
highly bound to plasma protein and are slo~ly
(a) Oral Sustained release tablets, spansule
released in the free active form, e.g. sulfadoxme.
capsules, etc.; drug particles are coated with resins,
3. By retarding rate of metabolism Small
plastic materials or other substances which
chemical modification can markedly affect the
temporally disperse release of the active ingredient
rate of metabolism without affecting the biologi-
in the g.i.t. Another technique (controlled release
cal action, e.g. addition of ethinyl group to
tablet/capsule; Fig. 3.8) utilizes a semipermeable
estradiol makes it longer acting and suitable for
membrane to control the release of drug from
use as oral contraceptive. Inhibition of specific
the dosage form. Such preparations prolong the
enzvrne bv one drnil can prolong the action of
action by 4 to 8 hours and no more, because ant.;tt er dru,g, e,g, ~- aHop urinol inhibits the
deQ;rntrrjr.m of 6--n-11::rcap topurine, ritonavir boosts
tht~:-Je:vcis :,f i:ndirn1vir. cilastatin protects imipenem
70%
-i r. ,hl
, ;\,j}1Py
drug Inert core O g 0
O
0
o 0
O .r:1•0 -n
1_ lH t;,,J:,•
,-,,.,
;,;......
.- ,r;v .;J.•~'·L,u:.;
.:io,"'"'' ,::. ". .... 1 .t \"..., •

0 0 0 0 0 0 0 0 oO 0

O
00.00
o
O
o~o
O

O
Q
o°'o o / 4 ~ o o
oo foo _\
O , ~· o 0
O O O
4 . By rfitm·ding rena~ excretion The tubular
oo ·'. 0 0O secretion of drug being an active process, can
o ➔a°olo
O
0
~ _. % ,, ~ ooJooo
be suppressed by a competing substance, e.g.
0 O
oo O
O
O \.0 0
O ,_,., 0
O
0
°o /
0 O OO
o o
o O O
o0
O O oO O
°o o0 o o
proben ec id prolongs duration of action of
o 0 o
0
Semipermeable 0
0
O
° O 0
0 O
o O o penicillin and ampicillin.
membrane O o

0.5 h 6h Targeted drug delivery devices

Fig. 3.8: Pattern of drug release from oral controlled Some new devices have been invented (and many
release tablet/capsule; 30% of the dose outside the
semipermeable membrane is released immediately, while
are under development) to localise and prolong
70% of the dose is released slowly through the membrane the delivery of the contained drug to a specific
over the next 4-8 hours target organ. The ones already in use are:

A
 :4
GENERAL PHARMACOLOGY

1. Liposomes These are unilamellar or 2 . Drug releasing implants The implant .

bilamellar nano-vesicles (60-80 nM) produced coated with the drug using special techniques a~~ ~
then placed in the ftar~et organ to provide .
by sonication of lecithin or other biodegradable
prolonged delivery o rrunute quantities of the
phospholipids. Since liposomes injected i.v. are
drug by slow release. Progestin impregnated \
selectively taken up by reticuloendothelial cells,
intrauterine contraceptive device (IUCD) afford s
especially liver and spleen, and some malignant
protection for upto 5 years. It is also being tried
cells, the dJug incorporated in them gets selectively
for other gynaecological problems. Antithrombotic
delivered to these cells. Liposomal amphotericin
drug coated stents (devices -placed in the
B is being used in Kala azar and some serious
cases of systemic mycosis. Antibody tagging of thrombose d coronary artery after balloon
liposomes is being tried as a means to target other angioplasty to keep it patent) are in use to prevent
r restenosis and failure of angioplasty.
I
!
specific tissues.
I
I

I
I. I rJr PROBLEM DIRECTED STUDY
l

3.1 A 30-year-old mother of 2 children weighing 60 kg was taking combined oral contraceptive
pill containing levonorgestrel 0.15 mg+ ethinylestradiol 30 µg per day cyclically (3 weeks treatment-
.I 1 week gap). She developed fever with cough and was diagnosed as a case of pulmonary tuberculosis
lf . I

after sputum smear examination. She was put on isoniazid (300 mg) + rifampin (600 mg) +
pyrazinamide (LS g) + ethambutol (1.0 g) daily for 2 months, followed by isoniazid (600 rri"g)
+ rifampin (600 mg) thrice weekly. In the 3rd month she failed to have the usual withdrawal
bleeding during the gap period of contraceptive cycle. After 10 days her urinary pregnancy test
was found to be positive.
(a) What could be the reason for failure of the oral contraceptive?
(b) What precaution could have prevented the un wa nted pregna ncy?

'
3.2 A 20-year-old patient weighing 60 kg has to be prescri ::i.ed an antiepilept ic drug (available
as 200 and 400 mg tablets) for generalized tonic-clonk Sf\;'\fff:':;, H1t": pharmacok inetic parameters
II and therapeutic plasma concentratio·n of the selectt!d dn.\r ,:,n~:
Target steady-state plasma e0ncentration {Cpss} .._ 0 rng/L
Oral bioavailability (F) ... 70%
I ··-· J.J!. L/kg
Volume of distribution {V)
'I _ 80 ml/hr/kg
Clearance (CL)
Plasma half life {t½) 15 h ours
-
What should _be th e loading dose and the daily maintenanc e dose of the drug for this patient?

I (see Appendix-1 for solutions)