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Distribution of Drugs
Protein Tissue-protein
bound Free bound dr~1g
drug drug
wa -~~~~~
~· · @ ◄ ► @ ......~~ @ ◄ •~
~ ~~
102 TRJBUTION Or DRUGS
BIOPHARI\IACEllTICS AND PHARMACOKINETJcs
ch-3 ors I03
which are polar. water-soluble and ionised at plasma pH do not cross the . rtant simple and specialized physiologic· L,
blood-brain barrier (Fig. 3.3). he JJTlPo . a1 •Jctrncr\ are:
t l. Simple capillary endothelial barrier
Since the e\tent to which a drug exists in unionised form govems the 2. Simple cell membrane barrier
distribution pattern, situations that result in al~eration °~
blood pH affeq
3 _ Blood-brain barrier
such a pattern: for example, acidosis (metabohc or resp~atory) results in
decreased ionisation of acidic drugs and thus increased mtracellular drug 4 . Blood-CSP barrier
concentration and pharmacological action. Op?o~ite is th_e influence of 5. Blood-placental barrier
alkalosis. Sodium bicarbonate induced alkalosis 1s som~tim_es useful in 6. Blood-testis barrier.
the treatment of barbiturate (and other acidic drugs) poisorung to drive
the drug out and prevent further entry into the CNS a?d promote their The simple capillary endothelial bar~ier : The membrane of capil-
urinarv excretion by favouring ionisation. Converse is true for basic laries that supply bloo? to most tissues is, practically speaking, not a
drugs:· acidosis favours extracellular whereas alkalosis, intracellular dis-
tribution. barrier to moieties wh1ch we_ call drugs. Thus, all drugs, ionised or
unionised, with a mol~cular size_ less tha~ 600 Daltons, diffuse through
11
/ case of polar drugs where permeability is the rate-limiting step in the capillary endothelmm and mto the mterstitial fluid. Only drugs
rhe distribution, the driving force is the effective partition coefficient of bound to the blood components are restricted because of the large
drug. It is calculated by the following formula: molecular size of the complex.
Effective Ko/w = (Fraction unionised at pH 7.4) (Ko/w of unionised drug) The simple cell membrane barrier : Once a drug diffuses from the
capillary wall into the extracellular fluid, its further entry into cells of
(3.1)
most tissues is limited by its permeability through the membrane that
The extent to which the effective partition coefficient influences
lines such cells. Such a simple cell membrane is similar to the lipoidal
rapidity of drug distribution can be seen from the example given in
Table 3. I. barrier in the GI absorption of drugs (discussed in chapter 2).
The physicochemical properties that influence permeation of drugs
TABLE 3.1 across such a barrier are summarized in Fig. 3.4.
Distribution of Acidic Drugs in CSF
Drug Capillary
Relative acidity Cell
Effective K0 1w Relative rate of wall
Blood membrane
at pH 7.4 distribution Extracellular fluid Intracellular fluid
ThiopentaJ
Weaker acid
Salicylic acid
2.0 80 Drugs of size less @ ~ @ Bulk flow
Stronger acid than 50 Daltons
0.0005
Lipophilic drugs @
@ Passive diffusion
thiopental distributes in CSF at a rate 80 times faster than
Thus,acid. 50-600 Daltons
salicylic
Polar/ ionised drugs @+ @• Active transport
Stereochemical nature of drug will also influence the distribution of size > 50 Daltons Carrier
characteristics especially when it has a tendency to interact with macro-
_molec~Jes like proteins . . 7:iss~e localisation of certain drugs may be an
md1cat10n of stereoselect1v1ty m drug distribution.
Fig. 3.4 Plasma membrane barrier and drug diffusion across it
Physiological Barriers to Distribution of Drugs
P Blood-brain
barrier (BBB) : Unlike the capillaries fou~d _in otber
A membrane (or a barrier) with special structural features can be a 8
o....
"'' · are hiohly spec1ahzed
of the body the capillaries in the brarn O
• • and
•.
penneability restriction to distribution of drugs to some tissues. Some of rnu ch less permeable
' to water-soluble drugs. Tl 1e bram bcap1lla11es
~~~
tz'
rr:i) )"- .
· of endothelial cells which are Joined
conszst to one ano ther y con nu-
LI~ @riit!1li!Wlilnllnmlla1mimF ~
10UTJON or DRU(;s
1 pJSTR 1'6
104 BlOPII \R~IACFlTICS .-\ND Pl IARM/\COKINET1cs (h··
l·apy·
for example, Parkmson1sm a ,1 ·
1 ... a... h
of the ' . . . ' .,__ ·"" c ar~ter /f'd fr,
011., r1r:hr imaa/111/ar ;1111ctio11s comprising ll'hal is called_ as th e blood. Part1euon
. f dopamrne m the brain, cannot be Ire- led b• ,..,
° h . a Y aurr mi ltra!1<
'I
brain barrier (Fig. 3.5). Moreover. the presence of special cells called d~Pd parnine as it does not_cr?ss t e BBB. Hence, levc.,d,,pa v.-htch ~
O
·" .-,, •icWt's and ;,.,rrocwes. which are the elements of th e_ supporting of the CNS where 1t 1s metabolised to dopamin . .... ·
rrate f d e, 1~ u ,cu in r
u,,uc r~;und at the base· of endothelial membrane, form a sohd envelope pene t Targeting o po Iar rugs to brain in certain cc d t
11nen • bl m 1 10115 ~h a
.iround the bram capillaries. As a result, the intercellular (parace~ular) rrea ur had always been a pro em. Three different approache, ha\e
0
pa,sage 1s blocked and for a drug to gain access from th e capillary rum . ·zed successfully to promote crossing the BBB by d
circul;tion mto the brain, it has to pass through th~ cell~ (tr'."1scellular)
been utl 11 . rugs·
(i) Use of permeat10n enhancers such as dimethyl ~ulphoxuie
r.uher than between them. (However. there are specific sites 111 the brain
(DMSO).
where the BBB does not exist, namely, the trigger area and the median
h\ pothalamic eminence. Moreover. drugs admini~te~ed intranasally may (ii) Osmotic disruption of the BBB by infusing internal caroud
diffuse directly into the CNS because of the contmmty between submu. artery with mannitol.
cosal areas of the nose and the subarachnoid space of the olfactory lobe). (iii) Use of dihydropyridine redox system as drug carriers to the
There is also virtual absence of pinocytosis in brain. brain.
In the latter case, the lipid soluble dihydropyridine is linked as a
carrier to the polar drug to form a_ p_rodrug that readily crosses the BBB.
,.._ Extracellular fluid of brain In the brain, the CNS enzymes ox1d1ze the c_l1hydropy.ridine moiety to the
1 - Glial cells polar pyridinium 10n form that cannot diffuse back out of the brain. As
~ Basement membrane
Astrocytes ] B a result, the drug gets trapped in the CNS. Such a redox system has
Pericytes a been used to deliver steroidal drugs to the brain.
Capillary endothelium B
Blood
Tight intercellular junction Blood-cerebrospinal fluid barrier : The cerebrospinaJ fluid (CSF,
is formed mainly by the choroid plexus of the lateral, third and fourth
ventricles and is similar in composition to the ECF of brain. The
Fig. 3.5 Blood-brain barrier capillary endothelium that lines the choroid plexus have open junctions
or gaps and drugs can flow freely into the extracellular space between
A solute may thus gain access to brain via only one of the two
pathways: the capillary wall and the choroidal cells. However, the choroidal cells
are joined to each other by tight junctions forming the blood-CSF barrier
1. Passive diffusion through the lipoidal barrier : which is restricted which has permeability characteristics similar to that of the BBB (Fig.
to small molecules (with a molecular weight less than a thresh- 3.6).
old of approximately 700 Daltons) having high o/w partition
coefficient. Cerebrospinal Fluid
2. Active transport of essential nutrients such as sugars and amino Ependymal cells of
acids. Thus, structurally similar foreign molecules can also pen- choroid plexus
etrate the BBB by the same mechanism. ===-- Tight intercellular junction
'0e eff~tive partition coefficient of thiopental, a highly lipid soluble +-- Extracellular fluid
drug 1s 50 times that of pentobarbital and crosses the BBB much more ~ ~ Capillary endothelium
rapidly. Most antibiotics such as penicillin which are polar, water-
soluble and ionised at plasma pH, do not cross the BBB under normal
Blood
0
Highly
lipid-soluble
t Open junction
circumstances. drugs
The selecti~e permeability of lipid-soluble moieties through the BBB Fig. 3.6 The blood-CSF barrier
makes appropnate choice of a drug to treat CNS disorders an essential
pJSTRJBUTION OF DRUGS
BIOPHARMACEUTICS AND PHARMACOKINETics Ch· 3 1()7
106
TABLE 3.2
• hi Ii id soluble drugs can cross the
As in the case of BBB, only hig Y P d 1 1· ·ct St ages during which Teratogens Show Foetal Ab normalities .
.
blood-CSF barrier with relative ease w
and partially ionised drugs permeate slow Iy.
hereas mo erate y 1p1 so]ubJ
A drua that enters the
th; bulk flow of CS
cs; - d
perio
Significance
Harmful effec1.1
. h"ah concentratwn as F Fertilization and implantation stage
slowly cannot ac hieve a 10 iven drug, its concentration · first 2 weeks Miscarriage
continuous!\ removes the drug. For any g F 10 Period of organogenesis
· always • · the CS . _ weeks ~eft palalJ, optic
the brain will be higher than ill . 28
. c0 r diffusion of drugs mto the CNS anct
atrophy;m_ental
Altbouah the mec harusms ,, . . . retardation, neural
~ . th d In some
CSF are smular, e egree of uptake may vary s1gnif1cantly. · b I tube defects, etc.
cases. CSF drug concentration • may be hiaher e .
than its cere
.
ra concentra-
. weeks onwards Growth and development
. e.g. sulphame th o~zo Ie and trimethopnm, and vice versa m other 8 Development and
non functional abnonnalities
cases. e.g. certain P-bloclrers.
Blood-placental barrier : The maternal and the foetal blood vessels It is always better_ to restrict all drugs during pregnancy because of
the uncertainty of thelf hazardous effects.
are separa ted by a num ber of tissue layers made
. of foetal tro~oblast
~ -
basernent mem brane and the endothelium which together constitute the Blood-testis barrier : This barrier is located not at the capillary
placental barrier. The flow of blood in the maternal and the foetal blood endothelium level but at_ sertoli~sertoli cell junction. It is the tight
vessels is shown in Fig. 3.7. junctions betwee~ the ne1ghbo_unng sertoli cells that act as the blood-
testis barri(!r. This barner restricts the passage of drugs to spermatocytes
- - - - - - . : : - - - - - - - - - +-- Fetal vein and spermatids.
~~
~t,~
ffi @ffl @W +-- Fetal artery
~
, , "-
Placental barrier (endothelium+
+-- connective tissue + trophoblast
ORGAN/ TISSUE SIZE AND PERFUSION RATE
mi mi~= @\"g®i•~b +syncytium) As discussed until now, distribution is permeability rate-limited in
~ +-- Maternal artery the following cases:
~~-~~
~ +-- Maternal vein (a) When the drug under consideration is ionic, polar or water-
soluble.
Fig. 3.7 Placental barrier and blood flow across it
(b) Where the highly selective physiological barriers restrict the
The human placental barrier has a mean thickness of 25 microns in diffusion of such drugs to the inside of cell.
early pregnancy that reduces to 2 microns at full term which however
In contrast, distribution will be perfusion rate-limited when:
does not reduce its effectiveness. Many drugs having molecular weight
Jess than 1000 Daltons and moderate to high lipid solubility e.g. ethanol, (i) The drug is highly lipophilic.
suJphonarrtides, barbiturates, gaseous anaesthetics steroids narcotic an- (ii) The membrane across which the drug is supposed to diffuse is
algesics, anticonvulsants and some antibiotics, cro;s the baC:.ier by simple highly permeable such as those of the capillaries and the mus-
diffusion quite rapidly. This shows that the placental barrier is not as cles.
effective a barrier as BBB. Nutrients essential for the foetal growth are Whereas only highly lipophilic drugs such as thiopental can cros_s the
transported by carrier-mediated processes. Immunoglobulins are trans- mo st selective of the barriers like the BBB, highly permeable capillary
ported by endocytosis.
wall permits passage of almost all drugs (except those bo~nd to plasma
An agent that causes toxic effects on foetus is called as teratogen. proteins). In both circumstances, the rate-limiting step is th e rate ~f
~eratogenecity is defined as foetal abnormalities caused by administra· blood flow or perfusion to the tissue. Greater the blood flow' faster is
flon of drugs during pregnancy. the distribution.
~~~
~-!BlbiDD lkYiiimJ? )~
EIL'TIO:s" OF DRCGS
pt~TRI 113
112 BIOPHARMACEUTICS AND PHARMACOKl:siETJcs
Ci l \\ hich btnd ~electiwh to e,transcu\ar t·
• ..
,nc (t.C- those t1nt ,ire less bound• • to blood issues. e.g. chlo-
[)rugs . .
can hbe dcte r- ~
ocrit is known. The extracellular flm"d (ECFJ - volume
. f("jU . . . . . components)
mined by substances that easily . penetrate ihe caprllary mcm ranc ,lnd •.11111 arent \ olumc of d1stnbutton larger tlnn th -. · ·
Ji;11c • . . . • . - . ' e11 real YOI•
· · ECF b t do not cross the cell 111c 111 . nf distrihutton. T 11c \ J ol such drugs is ·ih, 'l\'
rapidly distribute throughout the u . d SO 2 , .rnd in . • unt1 ,. , . -· · • •. s greater than
h Na+ Cl Br' , SCN .1n , 4 11111 u11n. , lrl'~ nr JB\\ \nlumc; lnr C'\,1111plc. chloroquin• l · .. , : .
c
branes, ,or e.g t e , · . h . . uh,t·1nn:, ·ire • ,I* 11 • . e 1.is ,1 , J ot
1 ' 111 11· ~ 1tcly I 5,000 lttrcs Such drugs \caw the bod\ ·\
,q>f1111'
mannitol and raffinosc. However. none O t csc ' ' ' 1111,
' • s ow1y
pletely kept out o f. t11c ce 11 s. The FCF - ,·olurnc, . c,.:l11J1ng
, pl.1,111a 1,
,Ill( I '
uc "',•c11c1 nlly more t11x1, than drugs ..
tint
•
do 11 l)t d.IS tn•b Ute
1 111
15 litres. 1·110• total bod,· ,1.1ter (1 B\\)II HI 1 u•II ,·an h<'
• deeply 11110 h!ld)' 11ss11cs
approximately
determme. d hy use . o1· st1hs1 · •lllcc,· that Jis1r1butt' t'qun I ) ~ r Ill. a ,, .tkr l•1l•111rs th t prn1h1cc -111 <11!<.!ratmn 111 hindin,,,::, of dru<>e tl1 bl 00 d
I )\l1'
compartments oI. thc hml). (bc11h intra- and c,tr.1cdlu ar • n>r l' i;. h,-;I\'•
,
- l ,,.1tc1
,, , (f!TO) •ind lipid ,oluhk ,uh,t.m,·t·, ip111lt'f1 l.,,
e 1c'1ill 111 ;111 111, /'('{/,I(' Ill vd and those that inl1Ul'l1''" ci.1 Ug
water (07.0). tnlialc< • ,sud1
. , ,,1, c,,u i tn 1., 1111 v,isc1ila1 eomp\ 111cn1s result 111 a decrease 111 \,J. Other
. ••
· ·
anllpynnc. . ·ri · ·a. ·lltrhr
1e 111 1, le , Jhud , nlumc 1, d,·It·m1111t • • d ,is th, d1ttl'r- 111 11
1> " g may 111 i111cncc V11 arc c.hangc5 111 t1s~uc perfusion and pcnnc-
cncc between II1c• ·1·11w , •'llld H'F ,olUlllt'
. fht' llltl':.ll'Cll11l:1r
'7 lluid rnct,11 s t1.t, 11111 ,,cs 111 1hc phy,,coc • h . I h
cm1ca c aractcnstics of the drug ,, g
· Iuurng
.,· II w.,c, ' 1/ ' 111 110d ct•II, is :tJ>pro,1111.lld) .. hll\'s. 1brht\", t 1
1' " · . · •· ·
volume 111c
·)llfll';ltll'll
•. 1. t'll'lllges
' .
111 the
I
hody
•
weight
•
an<l age ,md several disc·tse st·lles
• • (.. • t .
TABLE 3.5 \ 1 :trl'lll ,oh1m<.! ol d1~1nhut1on 1s expressed 111 litres and sometimes
Markers used to Measure the Volume in ht~~Kg bl,d) weight. The VJ of -.ariou~ drugs rnnges from as km as
of Real Physiological Compartments l litrc, (pl,isnrn volume> to as high as 40,000 lllres (much above the 1,1tal
Plm,wlogirnl !-1111d \fark,n Us,d Appro.\/llW/c' \'o/ume bod) s ,c) ~Ian) drugs have \' d greater than_ 30 lttres_, The Vu ts a
C11111parh111•n1 (/Ur,•~) charactens1i, nl each d~ur,_un~er normal condmon, and 1s altt:red under
condiL(lll~ that affccl d1stnbut1on pattern of the drug.
Plasma f,11ns 1'1Ut'. •:1Joc,an111c
green, I J , I. clbur'lm
METHODS FOR STUDYING DRUG DISTRIBUTION PATTERN
Er) 1hrncyt1•s Cr 51
f·xtr,1cl'llula1 IlmJ \,,n 111c1utio!1salllc ,~,ch.ind::, :,.;c,1 drug charactni1a11un ass:t) s are centr.il rn providing evidence of
lti-.c raffinose, mulm, mannnol the spccificit) and sdeL·tiYit) of dnig, It is lhu, e~sent1al to understand
and r~l'io1 soll'pcs of sele,.1ed the drug disrrihution pattern Ill drug d1s,·o,e11 StuJ1e~ for dctenntmng
,ms \J•, CI , Br . SO,~ I~ drug di,1rih11lllHl pattern 111clude, microdial)'"· ma" ,pcctromctr) and
Tola/ hnd) ,, atcr fkutcnu ..-, OJllde, ..::Ll'l)nne 42 imaging methods such ,b 11 hole bod) autorndiography and positron
emission lonwgraph) ( Pl•T)
Since the tracers arc not bound or negligrbl) bound to plasma or I. Mirrodial) ,b : I ht, !l\.'luuque rnvol,cs rnsertion of ,cry line
tissue proteins, 1hcir appJrcnt ,olumc of Jr,tnhuuon is s:une as their true II\ ing body, mostly mto fluid spaces, ,uch
probes 11110 till' tt"lll's ,1r tht·
rnlume of distnb111ion The situation 1s different v. ith most drugs \\ h1ch
as the CSI, and ,llha ntrru:dlulnr fluids \lihere possible. !'he prohcs
h111d to plasma pro1e1ns or cxtra,wcul.:r tissue~ or both. Ccrtalll .~ent.'r·
tunsi-1 of at k,ht t\\ o con.:-cntnc tubes, und a semipcm1c,ible membrane
al1.:a1io11.1 can he made regarding the apparent \olurne of d1stnbu11011 of
such drugs scp,11,uing them, p11s1twncd ,111.:h that .111 artificial extmcellular thalysis
fluttJ can he \)(111 I) infusl'd through the probe and p,1st the mcm~r_ane.
Drugs which bind sl'lcctnel) 10 pla~rn protc111, or other blood t.: 11 bouud dmg molecules in the tr~suc, surroun d 1nr the pn)b'c d1ltuse ·
components, e g warf<>1nn (I c. those th .. t arc less bou11d 10 Into the flo1\ ing di.ii) sate, 1, hrch as then collected for analysis. The
extra,ascular tissue.,), ha,e apparent ,olume of d1\tnh1111on hmnJtron ot th 1, tcchmquc 1<; us rn, ..isi,e n turc.
.,mailer than their true , olume of d1s1nbu11on. The Vd of su~h 2· i\tntrix-ussistcd laser de-.orption ioni111tion-mass spe~trom~t?
.
drugs lies berwecn blood ,olumc ..:nd TB\\ ,olumc (1 c. between
imaging (MALIH-MSI) : II rs used to study drug locahzatton w1t~m
6 10 42 litre.,); for example, \\artarin ha~ J vd of about JO hires. m1croe nv11011111ental tissue i;omp.trtmcnts. Th 111 sec
. t1ons of ammal t1s-
~~~
~-!BlbiDD lkYnml? \)~
sunoN OF DRUGS
prsTR1 I I~
11-1 RlOl'll.\R~I\CILfrl('S .\NIJ PII.\RM/\C'OKfNETrcs
Ch.) the capillary endothelium be considered. b-
01
·•'hY cann Wh Id b • •rner I!, d1 tr, :.i,:,n
,uc, .ire C\P,"<'d w pham1accu1ical drugs h) either spotting or submerg.
g. "'
f unbou
nd drugs?
. b . ?
at wou e the consequence or f, f ~
ate ,, drug bd 11
o a selecuve arner .
ing ~1 \I DI \ISi 1, then performed on the ussue lo localize been . d b . t d. "b ·
NaJlle the specialtze amers o 1stn ut1on of drugs.
drul!-d1,tnbu1,,,n p.111cms.
J. Autoradiography : In this approach, the radioactively labelled 10- ·be the anatomy and physiology of blood brain b· ",'L--
oescn amer. .,. """
Jrug ,ub,tan,·c under irnesrigation is administered to teS t ammals, usu- ii- cteristics of a drug are necessary to penetrate such a barrier"
chara .
J.!h- m1,c or rats. \\ hich are killed at suitable ume intervals, and frozen ? J-{oW do nutrients which are ~enerally polar, make their way into the brain?
,c;tion, of u,sues or of the whole body prepared. An image of the 1-· dru"s such as peruc1lhn normally do not cross BBB b t d
polar O . u o so m
radrauon 1, obtained by placing the sections next to a photographic I3• . gitis Explarn.
rnen10 ·
emubton. Thu,. if a whole body section is used , and the radioactivity is the wee approaches by which a polar drug can be targeted I b .
]4. Narne o ram.
,pecificall) localized in highly perfused. organs such as the lungs and
, D gs that penerrate the CNS slowly may never achieve adequate therapeutic
lner. the image will reveal this. Comparison wrth a normal photograph ru concenrrauons.
IJ · brain · Wh Y?•
of the slice i; used to identify which tissues contain the radioactivity.
Wh is the placental barrier not as effective as BBB?
Densitometry can be used to quantify the relative amounts of radioactiv- 16. Y .
ll). llus technique has been used to show highly-specific localization of In which periods drugs are particularly harmful to foetus in pregnant
17.
drugs in rissues. women?
4. Positron emission tomography (PET) : Synthetic radioactive _ How are body tissues classified on the basis of perfusion rate?
18
boropes (e.g. lie_ 13N, 15 0 and 18F) with atomic masses less than the _ Thiopental is a highly lipophilic, centrally acting drug. By which route
19
natural]) occuning stable isotopes have half-life values of 2-1 IO minutes should it be administered for rapid onset of action? Why? What is the
and emit positrons that interact with electrons to emit gamma radiation reason for its rapid termination of action?
that can be detected outside the body. The isotopes are generated in a 20. Which are the factors responsible for the differences in drug distribution in
cyclotron and incorporated into the drug molecules immediately before persons of different age groups?
the administration of the drug. PET scanning permits the production of 21. What are the va1ious mechanisms involved in the alteration of drug
images of live organisms including humans. distribution characteristics in disease states?
22. Define apparent volume of distribution. Why cannot the volume of
QUESTIONS distribution of a drug have a true physiological meaning?
I. Define : (a) disposition, and (b) distribution of drugs. Whal is the major 23. What are the various physiological fluid compartments of the body? \\'bat
mechanism for distribution of drugs and what is its driving force? are their volumes and how are they estimated?
2. Un/es~ distribuuon occurs, the drug may not elicit pharmacological response. 24. The tracers used to determine the volume of body fluids have Vd same as
faplarn. their true volume. Why?
3. Why rs_ disrribu_tion of a drug not uniform throughout the body? List the 25. How are the binding characteristics of a drug related to its Vd? Explain
factors rnfluencrng drug distribution. why some drugs have V d value larger than TBW volume?
4 - ';hat are the two major rate-limiting steps in the distribution of drugs?
26. It is better to express V d in litres/Kg body weight. Why?
Under 1.1,hat circumstances are they applicable? 27 - Can a drug have two or more V d values? Explain why?
5 Which physicochemical properties of the drug limit its distribution? 28 · The tissue/blood partition coefficient values of a drug and tissue perfuSion
6. Phenobarbita! and_ sal_icylic acid have almost the same K but the former rates are given in table below:
0I
shows extensive drstnbution. Why? w
Tissues Perfusion Rate Distribu1io11 r1,
7. What rs the influence of change in plasma pH O ct· t .b . f Ktlb Kr
n 1s n u110n pattern o a
be l
dru ? B, d K .
ase on P a values, whrch drugs are most affected and which will
east affected by a change in plasma pH?
Liver 0.8
B. What parameter h considered t0 · be t he driving Brain 4 0.5
force for distribution of
~M~
Muscle 8 0.035
Fat 40 0.03
~-!BlbiDD ~ )