THE IMPORTANCE OF STERIC, STEREOCHEMICAL

AND PHYSICO-ORGANIC FEATURES IN DRUG

METABOLISM AND DRUG ACTION
ARNOLD H. BECKETT

Department of Pharmacy, Chelsea College of Science and

Technology (University of London), London, S. W.3, U.K.

There are many examples which show that the introduction of a steric
factor near a basic or acidic group in a biologically active molecule can
modify greatly the character and duration of action of the parent molecule';
similar changes can result from the introduction of lipophilic or hydrophilic
groups at any position in the molecule. These introduced groups in addition
to altering the potential 'fit' at an active site in an enzyme or target organ,
can also alter the distribution, metabolism and excretion of the molecules
because of the attendant changes in values and rate of lipid solubility
characteristics. In the observed biological response in the whole animal, it is
difficult to assign quantitative aspects to the various influences except in the
case of differences in activity of those enantiomorphs which have been
proved not to be distributed differently; some approaches which may help
to clarify this complex situation will be described later.
A few examples, drawn mainly from work in my laboratories, will suffice
to show the influence on biological action of the introduction of even small
chemically inert groups into a biologically active molecule. Normethadone
has analgesic and antitussive action; the introduction of a correctly orientated
ac-methyl group to give (—)-methadone leads to enhanced analgesic activity',
whereas the incorrectly orientated group gives (H-)-methadone which is
virtually devoid of analgesic activity but in which the antitussive activity of
the parent is retained (Figure 1). Because the distribution and rate of metab-
olism of these enantiomorphs is very similar, the introduction of the
ac-methyl group may be regarded as enhancing or inhibiting the interaction
of the molecule with analgesic receptor sites depending upon the geometry
of the added group. The cough reflex receptors may be regarded as showing
little stereo-selectivity for the methadone enantiomorphs. Similar arguments
may be used to explain the differences in CNS activity of the isomers
produced by introducing a methyl group adjacent to the nitrogen centre of
fi-phenylethylamine to give the stimulant (+)-amphetamine and non-
stimulant (—) -amphetamine, since these enantiomorphs exhibit only very
small differences in their distribution and metabolism pattern in animals
and man2.
The introduction of a correctly orientated fl-methyl group into the
acetylcholine molecule, to give the L-(+)-isomer, has little effect on the ob-
served muscarinic activity but the incorrectly orientated group in the
(—) -isomer virtually abolishes activity (Table 1); the introduction of the
methyl group into the ac-position leads to substantial reduction of the activity
231
 ARNOLD H. BECKETT

÷CH3group
(CH3)2 NCH2C (CH3)2NCHCH2C—C

cH3

N or methadone Methadone
(-)- isomer enhanced activity
(+)- isomer much reduced activity

Figure 1. The effect of introduction of a steric factor in an analgesic.

in the (+)-isomer and virtual loss in the (—)-enantiomorph (Table 1 and

Figure 2)3. The (-+-)-fl-methyl isomer is not quite so good a substrate for
acetyicholinesterase as the parent, whereas the enantiomorph is not a
substrate; both enantiomorphs of the ac-methyl compound are equally good
substrates as their parent (Table 2). The introduction of the ac- or fl-methyl
group into butyryicholine has similar effects on the suitability of the com-
pounds as substrates for acylhydrolase4 with the exception of the greater
reduction in the case of the L-/9-isomer (Table 3). In these acetyicholine-type
compounds, steric factors will be the predominant ones because all the
molecules have similar lack of lipid solubility; differences in rates of metab-
olism in the whole body as well as differences in fit at 'muscarinic receptors'
may contribute to the observed differences in response. The size of the
introduced group in muscarinic compounds can be critical even when
distribution is not likely to be affected significantly, e.g. introduction of alkyl
groups into 'normuscarine' and 'normuscarone' (Table 4)3.
Steric factors can alter the relative emphasis of alternative metabolic
routes, e.g. steric factors in the vicinity of the basic nitrogen in phenothiazines
can alter the relative importance of N-oxidation by rat liver microsomes

Table 1. Muscarinic activities of acetyl-oc- and acetyl-/-methylcho1ine isomers

(Number of molecules equivalent to 1 molecule of acetylcholine)

Guinea-pig Ratio Cat blood Ratio

Compound .
ileum (+)J(—) pressure (-l-)/(—)
()-Acetyl-fl-methylcholine iodide 16 097 —
(+)-Acetyl-/3-methylcholine iodide 10 240 075 280
(—)-Acetyl-fl-methylcholine iodide 240 — 202 —
(+)-Acetyl-ce-methylcholine iodide 50 — 35 —
(-f-)-Acetyl-ce-methylcholine iodide 28 8 13 11
(—)-Acetyl-at-methylcholine iodide 230 145 —
(+)-Acetyl-ac methyicholine (ethiodide) 265 150 —
(+)-Acetyl-cc-methylcholine (ethiodide) 170 12 88 22
(—)-Acety1-c-methy1cho1irie (ethiodide) 2000 — 1900
Data from Beckett et at.
232
 SOME ASPECTS OF DRUG METABOLiSM AND DRUG ACTION
o CH3 CH3 0
1/ CH2/
CH3—* N )—CH3
N(CH3)3 (CH3)3N

L -(+)—Acetyl-13-methylcholine 0— (—)—Acety1--methyfthotine
(10) (21.0)

0 H CH3 CH3H 0

CH3\ (CH3)3NHCH3
D— (+)—AcetyH-methy1choLine L— (—)-Acetyt -i- methyfthotine
(28) (230)

Fgure 2. Configuration and muscarinic activities of acety1-x- and acetyl-fl-methylcholine

isomers.

Table 2. Rates of hydrolysis of acetyl-o- and acetyl-[-methy1choline isomers

by acetylcholinesterase at 37° at optimum concentrations

Compound [S] opt. >< Rates of hydrolysis

l0 at (acetyicholine = 100)

Acetylcholine 49 100
(1)-Acetyl-fl-methylcholine iodide 180 46
L-(+)-Acetyl-13-methylchOline iodide 100 54
D-(---)-Acety1--methylcho1ine — weak inhibition
(+)Acetyl-oc-methylcho1ine iodide 63 92
L-(-—)-Acetyl-ot-methylcholine iodide 67 97
n-(-+-)-Acetyl-oc-methylcholine iodide 67 78
Data frorri Beckett ci a!.

Table 3. Rates of hydrolysis of acyicholines by acyicholine acylhydrolase

Rate of hydrolysis
(butyrylcholine-100) using
Acylcholine
Purified horse enzyme Horse serum Human serum

Acetyl 44 46 47
Propionyl 71 — 69
Butyryl 100 100 100
Pentanoyl — — 80j
Hexanoyl — — 46t
Heptanoyl
L-Butyryl-cc-methyl
—
81
—
93
4t
93
D-Butyryl-st-methyl 66 78 79
L-Butyryl-fl-methyl 45 55 50
D-Butyryl-/-methyl 0 0 0
Data from Beckett ci a!. except where marked with a dagger.
1 Data from Davies ci a!.
233
 ARNOLD H. BEOKETT
Table 4. Influence of size of alkyl group (= 2-position in muscarine)
on muscarinic activity
(Cat blood pressure; number of molecules equivalent to 1 molecule of
acetylcholine)
2-Substituent Mu:arine Muscarone Dioxolane Furan

OH3 03 023 16 2
C2H5 — — — 120

Acetyicholine (R of acyl group = 2-position)

OH3 10
C,H7 3700
Data from Cohen el at. 1956; Fourneau e at. 1945; Waser, 1958, 1962.
= number of molecules equivalent to 1 molecule of acetylcholine.

while leaving ring hydroxylation and suiphoxidation virtually unchanged5

(Figure 3).
Although the quantitative importance of added steric and stereochemical
features can be established in isolated enzyme systems, and with somewhat
less precision in isolated preparations, the attendant changes which may be
produced in distribution and metabolism make it hazardous to rely ex-
clusively on observed relative biological efficacies of the molecules after oral
doses as a measure of relative molecule—drug receptor interactions. Even
consideration of observed changes in the metabolism in conjunction with
observed changes in biological response is fraught with difficulties in many
cases. For instance, the pH of the urine in man and animals can alter the
reabsorption through the lipid tubule walls of drugs in urine after glornerular
filtration (see Figure 4)5. Thus, molecular changes which alter the PKa values
of molecules or their rate of partitioning into lipids can result in changes in
biological half-lives and differences in their ratio of metabolite to parent

CR3

CH2CH2CH2N (CHS)2 H2H CH2N(CH3)2 CH2CH2CH2 N

(10) (1) (Otol)

XNC, CH2CH2CH2N (CH3)2 CH2CH2CH2N(C2H5)2 CR2 CH2CH2 NG

(10) (0) (Otol)

Figure 3. Influence of steric factors on the N-oxidation of phenothiazines by rat liver micro-
somes [all compounds underwent ring hydroxylation and suiphoxidation].
234
 SOME ASPECTS OF DRUG METABOLISM AND DRUG ACTION
A B C

Glomerulus

Proximal
tubule Active

-Loop of HenLe
Distal tubule
and
collecting duct

Figure 4. Schematic presentation of renal tubular mechanisms of organic base transport.

drug which are influenced differently by pH changes in the urine. The

following examples serve to illustrate this point.
Amphetamine excretion in urine in man shows fluctuations when rate is
plotted against time and these are a reflection of changes in urinary pH
(Figure 5); less reabsorption occurs in the tubules when the drug is sub-
stantially protonated and thus not lipid soluble. When the urine is kept
acidic (pH 4'8 to 5.0) by the oral administration of ammonium chloride, an
increased excretion of unchanged drug occurs and there is a smooth curve
when the rate of excretion is plotted against time (Figure 6); normal changes
in rate of urinary flow do not affect this smooth curve6' '. Similar pH depend-
ent fluctuations are seen in the urinary excretion of methylamphetamine
(and its metabolite amphetamine) (Figure 7) and these fluctuations are
likewise abolished when the urine is kept acidic6. Big differences occur under
different pH conditions in the cumulative plot of drug excreted against time,
e.g. see Figure 8 for methylamphetamine. The reabsorption of many drugs
which are partially ionized at physiological pH, and thus the duration of
their exposure to metabolising enzymes, is dependent upon urinary pH which
is itself influenced substantially by diet, exercise, time of day, etc. Hence
C 2 Subject:E.J.T.
V¼.

21 ,r\/'
j
Time,,h
Figure5. The influence of urinary pH and urine output on the urinary excretion of ampheta-
mine in man, after oral administration of 15 mg (—1--)-amphetamine sulphate (similar patterns
were observed in other subjects).
235
 ARNOLD H. BECKETT

46
a)
Subject T.M.J.

52

a
02
a)
C

0
Time,h
Figure 6. Urinary excretion of amphetamine after oral administration of 15 mg dexampheta-
mine sulphate (capsule) while under acidic urinary control [•—I, rate of excretion of
amphetamine; L1—[I1, urine output].

the significance of how changes in structure can influence metabolism of drugs

in the body can be completely obscured by changes in urinary pH values.
Methylephedrine is metabolised to ephedrine, which is less lipid soluble
in the unionized state than the parent drug, and also to norephedrine which is
water soluble in the unionized state; the pH dependence of excretion is
therefore substantially different in these compounds, despite the similarity of
their PKa values (Table 5). The ratio of the amount of unchanged drug to
metabolite in the urine therefore varies greatly with the pH of the urine
when methylephedrine and ephedrine are given (see Table 5)7.
Subject MR.
aJ c
0
0

0
ci)
Methylamphetamine a
aC
z
a)

Time,h
Figure 7. Effect of urinary pH and urine output on the urinary excretion of methylampheta-
mine (and its metabolite) in man, after oral administration of 110 mg (+)-methylampheta-
mine (similar patterns were obtained in other subjects).
236
 SOME ASPECTS OF DRUG METABOLISM AND DRUG ACTION
Subject E.IT.
B
C)
Li)

-o
m Acidic
urine
E
0a) 6

a)
ci
a)
11)
C 4
E
'0
a)
aE
(V
2
-c

Ia)

0 4 B 16

Time) h

Figure 8. Cumulative urinary excretion of methylamphetamine in man under varying

conditions of urinary pH after oral administration of 110 mg (±)-methylamphetamine.

The differences8 in the effect of pH of the urine in man upon changing the
excretion. of amphetamine and the less lipid soluble norpseudoephedrine,
possessing an additional alcoholic hydroxyl group, are shown in Figure 9.
The analogous relationship8 between the excretion of methylamphetamine
and its hydroxy derivative, pseudo-ephedrine, is shown in Figure 10.
Mephentermine is excreted primarily in man unchanged but there is
some demethylation to form phentermine. The ratio of metabolite to un-
changed drug excreted and the pattern of excretion8 depends on the pH of
the urine (Figure 11). When a drug is more extensively metabolised, the
ratio of drug to metabolite can be very sensitive to pH changes in the urine,
e.g. fenfluramine, which is de-ethylated to norfenfluramine8 (see Figure 12).

Table 5. pH dependence of excretion and the ratio of unchanged drug to

metabolite in the urine in the case of methylephedrine, ephedrine
and norephedrine

Average % dose recovered in 16 h (3 subjects)

Drug PKa Acidic urine Alkaline urine

ff05
M E N M E N

Methylephedrine 920 2712 6503 1065 a1—2 306 439 147

Ephedrine 9-47 2500 8341 672 1701 10-30
Norephedrine 9-44 2287 9182 8486

237
 11

a)
C
-o
ci)
-c
a
a'
0
-o
ci,
U)
8-c
c —.

C
0
U

z0,

0 6 18
Ti me,h

Figure 9.
Urinary excretion of norpseudoephedrine and amphetamine from a subject
following oral administration of (+)-norpseudoephedrine. HO ( 25 mg base) and (+)-
amphetamine. HC1 ( 11-05 mg base) in aqueous solution with (a) acidic urine control, and
(b) alkaline urine control [Norpseudoephedrine: 0—0, acidic urine control (pH range
— — —•,
469—508); alkaline urine control (pH range 705—812). Amphetamine:
A— — — A, acidic urine control (pH range 460—481); A—A, alkaline urine control (pH

range 718—825)].

0)
C
-o
a)
a
ci,
0
•0
ci,
U)
En

C
0
8?
U

ci,

0 6 12 16
Time7b
Figure 10. Urinary excretion of pseudoephedrine and methylamphetamine from a subject
following oral administration of (+)-pseudoephedrine. HC1 ( 25 mg base) and (+)-
methylamphetamine. HO ( 12-01 mg base) in aqueous solution with (a) acidic urine
control and (b) alkaline urine control [Pseudoephedrine: 0—0, acidic urine control (pH
range 465—498); •— — — •, alkaline urine control (pH range 7-45—8-05). Methylamphet-
amine: A—A, acidic urine control (pH range 4-59—4-82); A — — — A, alkaline urine control
(pH range 7-18—8-25)].
238
 SOME ASPECTS OF DRUG METABOLISM AND DRUG ACTION

/ \\
/
c0 / \\
\.- __\
a)
U
\
xc1 \
zci,
- ----
0 4 8 12 16 20 24 28 32
Time,h
Figure 11. Urinary excretion of mephentermine and its metabolite phentermine after oral
administration of 1411 mg mephentermine sulphate with no urinary pH control (a) and
acidic urine control (b) [Acidic urine control: O—--O, mephentermine; A----A phenter—
mine. No urinary pH control: • — — — •, mephentermine; A — — — A phentermine].

Ia 5
I, ..,_ _•
L ••_______•••%.,_ ,__•_•••'•••...##I_
uncontroUed trial)

C
E

74
C 3
0
a)
0 2
a' 0
U

za) 'C
U

0 4 6 8 10 12 14 16
Time, h

Figure12. Urinary excretion of fenfluramine and its metabolite norfenfluramine after an

oral dose of fenfluramine hydrochloride (20 mg) to a subject (L.B) under (a) acidic urine
control, (b) alkaline urine control and (c) pI-J of the urine not controlled [Acidic urine:
0—0, fenfluramine; s—LI, norfenfluramine. Alkaline urine: x—x, fenfluramine;
y—y, norfenfluramine. Uncontrolled urine: S ——--5, fenfiuramine; •— — —
norfenfluramine].
239
 ARNOLD H. BECKETT
It is thus obvious that meaningful investigations of the importance of steric,
stereochemical and physico-organic features in the metabolism of molecules
in vivo and on biological half-lives and on enzyme induction, etc. in man and
animals and biochemical differences between species, require the reabsorp-
tion of the unionized drug species in kidney tubules be minimised by suitable
pH control (and by diuresis in some cases).

10 100

r 8 80
4)
In
4)
U,
0
•0
0
0
C
6 60
a)
Ca
4)
C-)
C a)
0
0)
L 4 40
U
6) J
a) F
C-)

2 20

0 4 8 12 16 20 24
Time,h
Figure 13. Agreement between computer calculated and experimental excretion data for
amphetamine in man (constant acidic urinary pH).

Under these controlled conditions, it is not only possible to see the effects of
changes in the molecules or the formulation of the drugs but to consider
'models' for drug absorption, metabolism and excretion in the body. Since
intra-subject variations in results are thus very small, and inter-subject
variations are also small unless genetically controlled metabolism or diseased
states are involved6, analogue computer techniques can be utilised9, e.g. see
Figure 23, for amphetamine for single doses, and for repeated doses see
Figure 14. Thus the effect of changes in structure of the drug on the relative
importance of various metabolic routes can be established. From computer
calculations under conditions of acidic urine and then under normal con-
ditions of varying urinary pH (Figure 15) it is possible to establish the
relationship between pH and excretion (or reabsorption) of a particular
drug'° (see Figure 16) and then use an analogue computer to predict the
excretion profile of a drug when only the time and pH of the urine are
measured after the administration of the drug'1; agreement of predicted
values and experimental results are good (see Figure 17).
240
 SOME ASPECTS OF DRUG METABOLISM AND DRUG ACTION

10 100

a'
-c
OU 0
C, -o
In
0
-D
F C
6 60 .2
C, C,
(C
0 U
'C
C C,
0
C) 4 40
U
xC) (C

z
C)
2 20

0
0 4 8 12 16 20 24

Time h
Figure 14. Computer curves and experimental data points for the urinary excretion of
amphetamine, after oral administration, of divided doses of (-1- )-amphetamine sulphate in
aqueous solution (subject, A.C.M.).

From the foregoing, it is obvious that the rate of partitioning of drugs

across membranes at different pH values can have great effects on the
extent of metabolism and the distribution and excretion of drugs, and the
interpretation of observations on the biological effect of changes in drug
molecules. The use of partition coefficient experiments using buffered sol-
utions or the rate of passage of drugs through an organic phase between two

10

-c 8
C)
U)

00 6
U,
C)
'C 4

5 10 16
Time, h
Figure 15. Computer calculations of the rates of amphetamine as functions of time under
uncontrolled urinary pH conditions (subject 1) [presentation to the kidney, keB*; kidney
reabsorption, dR/dt; urinary excretion, dUJdt].
241
P.A.c.—It
Figure 16.
C
0
U)

U)

C
U)
U

a)
a-
100 0

10 OL7 50
ARNOLD H. BECKETT

log °/oEo -Qi383pH+038

55 60
pH
65 70 7'5

Relationship between log percentage urinary excretion of amphetamine and

measured urinary pH (data from 4 trials in 2 subjects).

I 70
0-

(U
6'
C
D

Computer predictions
—--—•—-- Experimental data
60
-c
U) U)
Lfl
0 0
D -o
4'O
ci) c
CU 0
U)
C 0
0
a)
2O
0 U)
>
U)
CU

6)
F
J
a—)

2 4 68 10 12 14

Time,h
Figure 17. A comparison of computer predicted and actual rates of excretion and cumulative
excretion of amphetamine after oral administration of 15 mg of n (+ )-amphetamine sulphate
in solution.

242
 SOME ASPECTS OF DRUG METABOLISM AND DRUG ACTION
buffered solutions is not completely satisfactory as a basis of consideration of
passage of drugs through biological membrane, since the relative order in
which members of a series of drugs are placed frequently depends on the
type of organic phase used. We therefore now use a human membrane for
these studies—the buccal one—and have introduced the 'Buccal Absorption
Test' as a means of classifying the relative partitioning of drugs from solutions
of differing pH values. Basic drugs were classified into four main tyçes on the
result of this test'2 (see Figure 18). Amphetamine gave a different shaped
0 (.1—Amphetamine L4 Norephedrine
90 • (+(—N1 ethylamphetamine A D—Norpseudoephedrine

o Chtorpheniramine x 1)-Nicotine
• (4-1-Methadone
81

'072
ci 63
0
4/
-o 54
(1

45

oJ 36
27

18

9
0
4 5
Buffer pH
Figure 18. Buccal absorption of some basic drugs representing different classes in the Buccal
absorption test.

curve from that of norephedrine, which is in accord with the pH dependence

between pH 5 and 8 of the tubular reabsorption of the former but not of the
latter (see Table 5); correlation between results in the buccal absorption test
and kidney reabsorption of many basic drugs has been established. The
relative order of partitioning of basic drugs is independent of the subject
used and many drugs can be placed in the mouth without mutual inter-
ference with the results in the test. The effect on partitioning of the intro-
duction of a lipophilic or hydrophilic group into a molecule can be readily
seen, e.g. introduction of the trifluoromethyl group into ethylamphetamine
to give fenfiuramine and introduction of the alcoholic hydroxyl group into
fenfluramine8 (see Figure 19). Similarly, the effect of altering the chain length
in N-substituted amphetamines can be seen readily8 (see Figure 20).
This test can be applied similarly to acids—the effect on partitioning of
the introduction of even one methylene group into a long chain acid is seen
even when all the acids have identical PKa values'3 (Figure 21). The effect of
altering lipid solubility without altering PKa values is also seen in a series
of p-alkyl or halogen substituted phenylacetic acids prepared for anti-
inflammatory testing (see Figures 22 and 23). The large difference between
243
 Fenfluramine
0 Ethytamphetamine
IV—2—hydroxyethyi norfenfturamine

8(

C
0
0
0U, 5'

U
OD

21

L.0 50 60 70 80 90 100
Buffer pH
Figure 19. The buccal absorption of fenfluramine, ethylamphetamine and .AT-2-hydroxyethyl-
norfenfIuramine within the pH range 4•O—905. Time period for absorption, 5 mm. 1 mg
(base) of each compound was used.

100

o Dimethyl
• Butyl
80 A Propyl
• Ethyl
o Methyl
V —

0
a
0U)
.0
C',

C',
U 40
U

20

3 5 7 9
pH
Figure 20. The buccal absorption of N-substituted amphetamines (subject A.C.M.).
244
 SOME ASPECTS OF DRUG METABOLISM AND DRUG ACTION
codecanoic
o Decanoic
x Octanoic
i Hexanoc
BC • Undecanoic
V Nonanoic
o Heptanoic
Vateric
A Butyric
6(
a
0U)
-U 40

20

5 7
pH
Figure 21. The buccal absorption of straight chain fatty acids (subject A.C.M.).

the p-tertiary butyl derivative 'Ibufenac' and phenylacetic acid (Figure 24)
and the difference between substitution with an alkoxyl group rather than
with the corresponding alkyl group (Figure 25) illustrates the importance of
these changes on the ability of the compound to pass through biological
membranes under various conditions'3.
The changes in the likely reabsorption characteristics of a metabolite
100

•H
CH3
• C2H5
o n-C3H7
A n—C4H9

'
o n—C5H11
n—C6H13

60
C
0
a
0
U)
40

20

3 5 7 9
pH
Figure 22. The buccal absorption of p-alkyl substituted phenylacetic acids (subject A.C.M.).
245
 100

• Ci
viBr
80 o

Q 60
0

0
1.0

20

3 9
pH
Figure 23. The buccal absorption of p-halogenated phenylacetic acids.

•H
Me
80 • Et
A t-Bu

d 60
0
0
0
(1
1.0

3 5 7 9
pH
Figure 24. The buccal absorption of p-alkyl substituted phenylacetic acids (subject A.C.M.).
246
 SOME ASPECTS OF DRUG METABOLISM AND DRUG ACTION

— Alkyt
Alkoxy
o CH3 and OCH3
8( • n-C3H7 and 0C3H7

3 5 7 9
pH
Figure 25. The buccal absorption ofp-alkyl and p-alkoxy phenylacetic acids (subject A.C.M.),

80
• Methadone
o Metabotite of methadone
70 produced by mono-N-
demethy [ation
• Pethidine
60 o Norpethidine
C
0
50

20

10

0
4•00 500 600 700 800 900
Buffer pH
Figure 26. Buccal absorption of some basic compounds.
247
 ARNOLD H. I3EGKETT
versus the parent drug in kidney tubules can be readily shown in the buccal
absorption test (see Figure 26); i.e. the ratio of the metabolites, norpethidine
and 'cyclic normethadone', to the unchanged drugs pethedine and
methadone in the urine, will increase greatly as the pH of the urine is made
less acidic'4, but this will not be the case for the metabolite, amphetamine,
from methylamphetamine (see Figure 16).
The steric, stereochemical and physico-organic features of drugs can thus
influence drug absorption, distribution, metabolism and excretion, and
therefore drug action and the duration of action in a complex inter-related
fashion. If we are to make further progress in structure—activity relationship
of drugs in the whole animal, it is imperative that we attempt to disentangle
the separate parts which contribute to the observed quantitative values of a
biological response.

References
1 A. H. Beckett. Arzneimittel-Forsch. 1, 455 (1959), and refs. cited therein.
2 A. H. Beckett and M. Rowland. J. Pharm. PIzarmac. 17, 628 (1965).
2 A. H. Beckett. N.Y. Acad. of Sci. 144, 675 (1967), and refs. cited therein.
R. 0. Davies et al. Canad. J. Biocliem. Physiol. 30, 545 (1960).
A. H. Beckett and D. S. Hewick, to be published.
'A. H. Beckett and G. T. Tucker. J. Mond. Pharm. 3, 181 (1967), and refs. cited therein.
'A. H. Beckett. Dansk. Tiddskr1ft. Farm. 40, 197 (1966), and refs. cited therein.
8 A. H. Beckett, to be published.
'A. H. Beckett and G. T. Tucker. J. Pharm. Pharmac. 20, 174 (1968).
10 A. H. Beckett, R. N. Boycs and G. T. Tucker. J. Pharm. Pharmac. 20, 269 (1968).
11 A. H. Beckett, R. N. Boyes and G. T. Tucker. J. Pharm. Pharmac. 20, 277 (1968).
12 A. H. Beckett and E. J. Triggs. J. Pharm. Pharmac. 19, 31s (1967).
13 A. H. Beckett and A. C. Moffat. J. Pharm. Pharmac. (1969), in the press.
14 A. H. Beckett and J. F. Taylor, to be published.

248