Human Pharmacokinetics and Comparative Bioavailability of Loperamide Hydrochloride JOANNE

hydrochloride,

OPERAMIDE

phenyl) a,a

4

-

-

diphenyl

-

-

N,N

dimethyl

-

-

Imodium,*

is

a new

which is used for symptomatic reand control of acute, nonspecific

diarrhea

and

with

chronic

diarrhea

inflammatory

structural

formula

chloride

associated

bowel

is shown

of

HOWARD S. WEINTRAUB. BARBARA L. FULLER.

In

disease.

The

loperamide

below:

loperamide

transit and

trolyte ing

the

in

man

rapidly

peristaltic

loperamide isotope

from

ileum. tivity

This inhibition is considered

on

the

intestinal

pared

doses

which

tivity

and

in

nervous

appears

to

diarrheal

be

agent

di-

antidiarrheal

analgesia

is

in

com-

loperamide between

produce

the

aceffect

When

which system

pig

codeine,

produce

Since

central

of peristalic be a direct

morphine,

those

rats.’

guinea

and diphenoxine, largest separation

the

showed

to

muscles.’

with

phenoxylate,

inhibition

in the

this

of

loperamide specific

group

of

the

Biochemical

Pharmaceutical

Corporation,

velopment, *

Raritan,

Ortlio

Trademark,

Raritan, April

Research

N.J. 1979

N.J.

Division, Research

and Corporation,

was

fluids.5

ducted8

using

the

for

of

of

loperamide

com-

The

a specific,

the

study, was 10 hours

study

elucidate

reported the

chloride

after and

syrup

It

for

quanti-

highly

sensi-

oral

de-

loperamide study

in

was

con-

radioimmunoassay

in

measurement

of

of loperamide

therapeutic

range.

the

half-life to be ap-

apparent

determined

In

in man. here

was

designed

pharmacokineties to

was

method

procedure was the quantitative

A limited

compound and tive bioavailability sule

an to

unmetabolized

pharmacokinetics

second

used

this

specificity

this

above

this

studies. 1974,

that

a preliminary

human doses

different

40 hours.

unmetabolized

biologic

anti-

De-

required

of

proximately

Ortho

08869.

Pharmaceutical

study

Later,

analysis

two

hydrochloride and dilution technique

tive radioimmunoassay veloped which permitted

to From

the

defin-

separate

determined

loperamide.

at

a measure

effects, most

ac-

elec-

loperamide

in

measurement

1977

analgesia

fecal

and

of unchanged loperamide. apparent half-life result-

this

tative

in

in two conducted

subsequently

induces

reflex

increases

with of

resulted

study,4

lacked Loperamide

concerned

determined

monitor levels The reported

of the

amd N.J.

daily

fluid

half-life

had

values

ing

lowers

diminishes studies

inverse

(\ij

1101

time,

apparent

tritiated

#{149}HCI

Ph.D.. Rartan.

loss.3

Previous

One

hydro-

man

intestinal volume,

piperidinebutyramide

-

monohydrochloride, drug lief

-

Ph.D..

pounds.

4- (p-chloro-

hydroxy 1

M. KILLINGER.

measure the of loperamide

of

administration

formulations.

the

comparahydroof capThis

study 211

KILLINGER,

was conducted therapeutic specific

using range

WEINTRATJB,

doses within employing

and

radioimmunoassay

the the

previously

AND

FULLER

tion. Subjects from midnight ministration

de-

veloped.

tration

the

of

Sample

Materials

and

Methods

Materials. 4-

(p

-

Loperamide

dimethyl

a,a

-

butyramide and

hydrochloride,

chlorophenyl)

its

diphenyl

-

desmethyl -

14425) rabbits

to

albumin

conjugate (specific

and

activity

serum

capsule

and

loperamide

1101

loperamide

1101

a 0.2-mg/ml

syrup reference preparation. Subject Selection. The

subject

tion

volunteers

consisted

36

to

well

43

of six

years.

normals

cal

hepatic

of

for

two

aged

The

physiand

subjects

and

denied

weeks

prior

taking to

or

medica-

starting

the

Drug

During

Administration.

crossover

study

each

subject

of

loperamide schedule.

both formulations ing to a randomization jects received of loperamide mg/ml followed terval ministered. subject loperamide ounces libitum, beginning 212

either 1101

syrup. by

or

Each the After

ingested HC1

other an a

accordThe sub-

single

after

serum

ainide

using

(Pentex), used

standard

frozen

until

they of

loperamide

curves

in

was The

meas-

proceof loper-

generated

or urine was same procedure

samples modified

in

detailed was used

analysis extraction

of

8 mg

spiking

the

8

approximately minute of tracting volumes

serum

was buffer.

of or

the

urine

lopersamples

of radioimmunoassay. technique consisted

serum

or

urine

sample

5000 disintegrations 3H-loperamide and

each of

aside)

phosphate

extraction

the

before This

sodium the

were analyzed by a technique which in-

ether

each

ad

0.1% of

fast,

administra-

samples

place

ad-

drug

urine

and in

an

by

ad-

For

were

frozen

of

The

from

followed

adminisdrug

samples

content

serum

amide

was

after

radioimmunoassay. the radioimmunoassay

volved

dose

before

stored

and

by for

in-

of water. Water was allowed and a normal diet was permitted 4 hours

The

was was

day

Radioimmunoassay

Samples.

treatment

overnight

which

this

treatment

the

in this study except that RIA buffer (0.1M sodium phosphate, pH 7.0, with 0.9% NaOl, 0.1% bovine gamma globulin

received

washout

and

the sera by urine speci-

individually.

urine and

Selected slightly

a 14-day

clot,

and

stored

and

2-mg capsules ml of the 0.2-

drug

at least

before

four 40

to

from 24-hour the

and

control previously.6

study.

The

be analyzed.

ured dure

showed renal,

hours.

urine samples were collected 6, 8, and 10 hours. All other within the first 24 hours were

serum

the

blood

48

in nonheparinized

drug,

Loperamide

be

and

2, 3, 4, 5, 6, and 7, urine was coland pooled as 24-hour specimens.

could

to

a prestudy

gastrointestinal,

disease

days lected All

popula-

judged

hematology

profiles.

evidence

tion

on

included

chemistry no

were

based

which

the

sambefore

at the following 2, 3, 4, 5, 6, 10,

allowed

collected of

immediately

male

They

was

collected com-

36,

collected separated A

ministration at 2, 4, voidings

were

24,

blood

immediately and 1, 1.5,

were

tration

3H-loperamide

2-mg

20,

samples

men

9 Ci/mmole)

available

16,

Phar-

supplied by Janssen Pharmaceutica. two formulations used were the

mercially

administration thereafter:

(ORF produced

a loperamide-bovine

drug times

cells were centrifugation.

-

Venous

obtained

containers

a,a

-

Janssen

Antisera

were

12,

to smoke drug adadminis-

dose.

Collection.

ples

blood

4- (p-chloromethyl

-

by

Belgium.

-

Imodium, N

-

N,N

-

piperidine-

-

metabolite,

supplied

maceutica,

also The

1

-

-

were

HC1

hydroxy

-

monohydrochioride,

phenyl) 4 hydroxy diphenyl-l-piperidinebutyramide

in

4

-

were not permitted the night before until 4 hours after

sample

diethyl

The Journal

twice

ether

of Clinical

per ex-

then with

(Baker,

of with

three Photrex

Pharmacology

LOPERAMIDE

grade).

The

ether

extracts

PHARMACOKINETICS

were

com-

bined, dried under N,, and reconstituted in RIA buffer. The radioactivity in

ali-

quots

was

of

the

reconstituted

quantitated efficiency

of

of the

to

obtain

each

sample.

reconstituted

in

serum

efficiencies factors

each

urine. the

of

was

done

developed

by

Giles

Rodbard

of

the

the

both

trapezoidal

con-

in

the

most

of

the

loperamide

in samples ment sayed.

and

David

Institutes

from

of

two

loperamide

subjects

sulfate

conjugated

Analysis

of

to

centration

the

The with 0.1M

in

4.9.

These

rate the the

Trademark, N.Y. 1979

pharmacokinetic loperamide

rate the

constants apparent maximum Endo

paserum

times

The fit the

best using

culate

April

samples.

at various

pharmacokinetic termined

*

measured

Pa-

data

administration. model which

City,

and

has

was

noted

con-

after

constants

drug

were

computer

the

were

used of

of using

and

compari-

of the

areas

of

graph

method).

Antisera

antisera

has

our

laboratories

in

reported.#{176} In

of the

there

was

loperamide

metabolite further

that

report

it

cross

re-

with

the

antisera

found assay

to

experiment

of concentrations

been

some

of loperamide, quantitate the

metabolite with the

following

ORF amount

of

cause loperamide,

was

performed.

(10

to 5000

ference

in

the

amount

when ORF

of

was

1

500

added

ng dif-

loperamide

approximately

14425

in-

ng)

14425 was assayed with There was a significant

measured more

Loperamide

ng

to the

or

assay

mixture. This indicates that ORF 14425 must be present in a ratio of approximately 500/1 (ORF 14425/loperamide) before it will interfere loperamide. Thus, it antiserum very

employed

specific

for

with the assay appears that in

these

of the

studies

is

loperamide. of the

Two

Radioimmunoassay

of

Methods

for

Loperamide

deIn

to

cal-

elimina-

concentration Inc.,

the

that

Comparison

program.

half-life

Laboratories,

weigh

de-

Areas

rectilinear

of the

been

of this terference

pharmacokinetic data and various

serum

and

of

desmethyl 14425. To

of ORF loperamide.

The used

the

on

previously

A series

Pharmacokinetic

from

cut

to

measured

weights

specificity

the

Serum Samples. computer program8 was

determine

rameters

tion,

The

free

of

AUTOAN

were

plotted

Specificity

either

was

pH

used

bioavailability formulations.

Results

so that

as

hydrolyzed 48 hours

buffer,

treatalso asto free

was

urine

acetate

rameters

was

loperamide

hydrolyzed

sodium

at one

esters

urine samples were Glusulase* at 37#{176}Cfor

only however,

conjugated or

the

samples,

measured,

hydrolyzed urine urine hydrolysis

glucuronide in

urine

was

each, The

plus

(the

action

For

any

paper

also

integration

relative

curves

measured

Health.7 free

of the

concentration-

were

curves

these

sam-

program

Frazier

National

son of

radioimof the

a computer R.

under

loperamide

loperamide

serum

maxi-

correction

For both calculation

using

the

curves

radioimcurves extraction

as

under

analyzed

instead

The used

sample. techniques,

concentration ples

buffer

then

in calculating

tent of munoassay

were

Areas versus-time

at which the occurred.

termine the comparative the syrup and capsule

aliquots

using standard

RIA

or

were

extraction

Other

content which the

generated

control

the

samples

for loperamide munoassays in were

samples

obtained, and the time mum serum concentration

Garden

used The

the

current

study

two

for radioimmunoassay first method involved

standard urine, called validation

and

curves in control in this discussion

the of

nonextraction this method

methods

were

of loperamide. generating serum it will method. in our

or be

The labora213

KILLINGER,

WEINTRAUB,

AND

ing

FULLER

the

aliquot

sizes

standard measurement

curves.

pendent chemical

of volume entity was

were

parallel

This indicates loperamide

of

to the that

the inde-

was

1

II

the

sample

and that the being measured

aliquots

as

curves. If interfering present, the resultant been nonparallel. When control assay.

I

Fig. 1. Representative serum concentration after

capsule

plot of logarithm of loperamide vs.

of time

administration.

the

study

was

using

results

pools.

The

of

conducted,

the

9.4%

quality

of

coefficient for

both

been have

with each calculated

analyses

intra-assay

was

standard

had would

pools were measured The assay variance was

tion 1

the

in

substances curves

same in

these

of varia-

methods.

The

interassay 17.0% for

coefficient of the nonextraction

variation method

was and

18.1%

for

the

method.

data tained

suggest using

extraction

These

that the measurements either method are

obcom-

parable. tories

was

second

discussed

method

tion

of

previously.6

involved

loperamide

an

from

ether or

the

curves

second

will

buffer.

be called

the

Experiments termine

if

parable

results.

ard for

extraction

these

curves both

of

The

were

Comparison

urine

extracts standard

of the

Formulations in

The syrup

method to

methods

gave

comparative

bioavailability

and

formulations

termined

capsule utilizing

ranges

serum

or urine, measured

amide

pared

to the

gave tion

comparable coefficients

extraction traction

of

amounts ing

amount

the

ng of

were

aliquot

percent bound both methods, 214

control

amount method

added.

human

sizes

dethe

_L_ ....

1.#{149}

sv

methods

I..

for the interfering

were from

versus curves

under

of loperwas com-

Both

and 0.997 As a test for

generated

areas

the

.

1

S.

results, with the correlabeing 0.993 for the non-

loperamide

of was

stand-

various aliquot sizes or urine containing of

these

to

and the by each

method method.

substances, trol serum Curves

added

the

Syrup Data

de-

,

were

and

Serum

com-

were generally 0.05 to 10.0 methods. Known amounts

loperamide

Capsule

Using

method.

performed

two The

extrac-

serum

samples, reconstitution of RIA buffer, and generation in RIA

The

by aliquot generated

S.. S.,

exS..

‘.4

of conknown

S..

measured. data

I,

plotting

the

size. For by vary-

10

T

employFig.

serum after

2.

Representative

concentration syrup

(N0110$)

plot

of

of

loperamide

logarithm

vs.

administration. The

Journal

of

Clinical

Pharmacology

of

time

LOPERAMIDE

TABLE

I

Areas Under the Serum Concentration-Versus-Time Method Treatment

*

(ng

.

PHARMACOKINETICS

area measurements iologic availability

Loperamide Curves*

1

lation is formulation.

Method 2 . hr/mi)

Based

(ng

hr/nil)

indicate of the

equivalent on the

loperamide

to that observed

26.1

3.7

25.2

±

3.5

the

Syrup

26.9 ± 3.7

27.2

±

3.7

rapidly than from tion. The mean (± mean) serum level

areas

The

error

are

given

of the mean.

of the 2 was

weight of trapezoidal

the

I was areas)

relative

± standard

means

as

Method

determination and

syrup

5.2 ± serum

loperamide

time

curves

tion

of

curves These

the

are

dosage

are data

methods

concentration-versus-

determined in Fig. compared

area

shown

in

1 and using

analysis,

Table

I.

and The

results

The

tions

of

0.42

of the

for

data

of the

trations

at

Apparent

Treatment

(hr-i)

1-1

capsules

0.0732

1-2

syrup

2-1

syrup

2-2

the

serum from

absorbed

more

2.4 ± 0.7 time was

capsule

formula-

serum

were

concentra-

similar

maximum

for

the

for

serum

various

capsule

con2.24

was ±

formulation.

loperamide times

both

serum

syrup formulation compared to

for

concen-

for

each

of

the

of Loperamide

Malf-Life

Apparent

Eei

no.

for

loperamide

II

Biologic

Subject

syrup

was peak

peak

The

ng/ml

the

the capsule formulastandard error of the peak time observed

loperamide

The

results

TABLE Estimation

hours observed

centration for the 2.19 ± 0.36 ng/ml,

Fig. 2. the two

the

0.3

tion.

was

formulation the mean

formulations.

administra-

Representative

forms.

shown were

of

after

formulation

for the syrup hours, while

method

integration.

of

values

concentration,

Capsules

±

that the physcapsule formu-

t

(hr)

r2

9.47

0.981

0.0760

9.12

0.989

0.0593

11.69

0.985

capsules

0.0739

9.38

0.986

3-1

capsules

0.0612

11.32

0.972

3-2

syrup

0.0750

9.24

0.988

44*

capsules

4-2

syrup

5-It

syrup

5.2

capsules

6-2

caspules

-

-

0.0640

-

10.83

0.963 -

-

-

0.0481

14.41

0.963

0.0599

11.57

0.979

syrup

Mean *

The

data

did

points

in the

I The

data

using the *4 The t

April

1979

±

10.78

S.E.M. not

absorption

fit a computer-generated

pharniacokinetic

±

model

0.57

because

of

some

judged

to

be

irregular

phase.

fit test

a two-compartment of extreme values.9

was

judged

model

to be an outlier

and

using

the

t

the test

generated

was

of

values.9

extreme

an

outlier

215

KILLINGER,

WEINTRAUB,

AND

TABLE Amount

of Loperamide

Excreted Subje

III in the Urine

Free

(hr)

subject

Subje

0.005

0.012

0.068

0.086

0.048

0.063

0.184

0.215

6

0.149

0.167

0.339

0.392

0.249

0.402

0.480

0.316

0.477

0.568

24

0.323

0.460

0.830

1.082

48

0.591

0.787

1.381

1.725

72

0.620

0.863

1.406

1.783

96

0.620

0.890

1.411

1.804

120

0.620

0.890

1.411

1.813

144

0.620

0.890

1.411

1.815

168

0.620

0.890

1.411

1.815

cumulative

times

were

the

formulation. from

constants

also

is capsule

calculated 2.15 ± 0.29 ± 0.25 ng/ml the

lower capsule

computer-generated values are presumed 216

administered

model of

Estimates

by

concenthe rate

the

syrup

absorbed The maxi-

concentrations

values, to be

the

peak

heights

using

the

the observed the more cor-

peak

are

height,

calculated

elimination the

The

as

based

model apparent II.

tion

high

are

rate

the upon

constants

computer

coefficients measure

a

in Table

ob-

program

data

of determination, of how well

the

fits the data, and the calhalf-lives are presented

The

coefficients

of determina-

(0.963-0.989)

and

indicate

that the computer model fits the reasonably well. The mean apparent life of loperamide after administration the

for the syrup and the capsules. Since

formulation

using

computer culated

that

point.

estimates of rate constants. The apparent biologic half-life of elimination for loperamide was determined

for the syrup hours for the times

time

of

values

are

computer

each

estimates

former

analysis. which

more rapidly formulation.

calculated

rect

at

peak

the

serum

reported

from

Calculated

indicate

is

tained

Thus, the peak computer-generated

ng/ml for

by

The fits the

open serum from

data.

the

dose

analyzed

program. that best

1.8 ± 0.4 hours and 4.3 ± 0.5

mum

for

also

absorption.

obtained

were

of

one-compartment

were

1.65

cent

computer model

of

times were formulation

there

per

and maximum were calculated

constants

formulation than the

(%ofdose)

0.241

first-order

rate

(%ofdose)

0.195

peak

capsule calculated

(%ofdose)

and

conjugated

8

with

analysis

Free

Free

4

the

trations

ct 2-1

2

treatments

was

Times*

and

conjugated

(%ofdose)

the AUTOAN pharmacokinetic data

Various

10

The

*

after

ct 1-1 Free

Time

FULLER

syrup

hours

formulation

(mean

±

sule formulation, it appears that loperamide two

after

formulations

was

S.E.M.) the

and

11.2 ± 0.8 apparent administration are

not

data halfof

10.2 for

±

the

0.6 cap-

hours. Thus, half-lives of of significantly

different. The

Journal

of Clinical

Pharmacology

the

LOPEIIAMIDE

Comparison

of the

Formulations The at

urinary times

were

also

from

drug

determined.

was

Peak

in

the

urine

per

ministered

seven

(mean dose.

formulation for the per

in

cent

cent.

days

±

The

was capsule

for excre-

hours. excreted

was

S.E.M.) mean

1.00

±

of the for

1.04 ±0.12 formulation,

Thus,

points

assayed

loperamide

48

the

ad-

syrup

per cent 0.97 ±

approximately

and 0.17

1 per

cent

of the drug was excreted unchanged in the urine after administration of either formulation. Hydrolyzed urine, which allows

measurement

and

the

conjugated

assayed (Table an

of

for

both

the

two subject The hydrolyzed

III).

increase

unchanged

loperamide,

in

total

than 1 per cent in both cases.

was

aiso

treatments urine showed

loperamide

of the

of

less

administered

dose

of this study was to adethe apparent biologic halfin man. Using a specific

hours.

This

value

to

bility

of

objective compare the

reference

amide

of the

the capsule

after

form

formulations, April

half-life 10.8 ± the

of 0.6

10-hour

present

1979

areas

absorption

relative bioavailaformulation The

were

curves

administration compared.

were indicating

It was

similar that

in

of each for the

found the

two

capsule

ab-

more

rapidly

from

than

from

lation. capsule nomenon

serum with

level also the capsule

mum

serum

similar ing that serum liquid

the

liquid

capsule

was found formulation.

formu-

levels form those

sule

dosage

that

a

later maxi-

observed

formulations, differences

were indicatin peak

after administration of are likely to be encountered of

the

clinically

form.

syrup

efficient

These

results

formulation

comparable capsule

the phepeak

to occur The

concentrations

with both no substantial

from

the

the

The slower absorption from may reflect a dissolution of the capsule contents. The

to

dosage

that

form

a

capsuggest

should

have

observed

with

in

humans.

Summary

chloride

(Imodium)

six

subjects.

male

random

crossover

a 2-mg

capsule

study loperamide

of

was The and

a

antihydro-

conducted

study

design Eaeh

the

in

utilized

and

a

employed

0.2-mg/mi

treatment

syrup consisted

of a single oral dose of 8 mg loperamide IIC1 followed by a two-week interval bethe

next

treatment.

obtained

specific

reference

the

formulation

half-life, phase

for

for for hours from

the

the

drug.

the

data, overall syrup

for the the syrup

than from the the peak serum

and

various a

calculated of the log

versus-time

Serum

at

drug administration loperamide using to

phase,

is absorbed

samples

study

availability

from the comthat loperamicle

fore

reported,

concentration-versus-time

the

the

formulation.

used was an oral soareas under the serum loper-

subject

dosage

that

with

formulation.

formulation lution. The each

agrees

as

serum

study.6

A second

a

intensive

in a previously

obtained

high-dose was

and

the mean biologic was determined

half-life

in

A pharmacokinetic diarrheal agent

radioimmunoassay sampling, loperamide

physiologic

to this reference dosage form. on a limited number of data

sorption constants, obtained puter data fit, indicated

safety

Discussion One objective quately define life of loperamide

had

comparable Based

administra-

occurred within the first mean amount of loperamide

0.10

formulation

Nonhydrolyzed

subjects

drug.

Syrup Data

concentrations

after

all

unchanged

tion The

and Urine

loperamide

various

tion urine

Capsule Using

PHARMACOKINETICS

was

formulation,

after

were assayed radioimmunoassay The

from serum

study,

urine

times

mean

for biologic

the elimination concentration10.8

±

0.6

hours

10.2

±

0.6

hours

11.2

±

and

0.8

capsules. The loperamide was absorbed more rapidly capsule levels

formulation, with observed at a mean 217

KILLINGEB,

time

of 2.4

5.2 ± tion.

±

0.7 hours

0.3 hours for The relative

the

serum loperamide time curves suggested lations

the

of

the dose loperamide

observed dosage

form

capsule formulaareas under the

that

observed similar,

of the

syrup

formu-

of

the

3.

Package

Insert,

4.

1976. Heykants,

the

6.

administered.

Weintraub, kants, Studies

J.,

P. A. J., and (R18553), A agent, part

7.

1641 2.

Arzeim.-Forsch.

8.

(1974).

Niemegeers, Janssen, a

novel

I:

in

toxicity, codeine,

218

peristaltie reon isolated (Drug Res.) 24

C. J.

E.,

P. A. J.: type

vivo

of

oral

Lenaerts,

Loperamide antitharrheal

pharmacology

F.

M., and (R18553), agent, part

and

acute

man

after

oral

doses 21:867

Res.

with

morphine,

9.

Hinchen, Chemical

diphenoxylate

and

difenoxine.

Great

in (Drug

A.

J., A

J.

and of

administration

of

in-

Curr.

of Imodium. (1977).

and Rodbard, D.: A LogitProgram; Radioimmunoassay

R.,

3rd ed., Branch, Bethesda, and Decision

cokinetic Computer of Michigan, Ann

comparison

loperamide

J. M., HeyJaffee, J. H.: rate of loper-

G. RIA

Sedman, AUTOAN,

a

H. S., Killinger, Kanzler, M., and on the elimination

Data Processing, duction Research tutes of Health,

3: in vitro studies on the flex and other experiments

tissues.

Frazier, Log

5:

Life

in

R.,

A., and

(R18553), agent, part

Heykants, the antiSci.. 21:451

Therap. J. M., Janssen, J.: Loperamide of antidiarrheal

of

Michiels, M., Hendricks, J.: Radioimmunoassay diarrheal loperamide. (1977).

N.J.,

Knaeps,

and man. Arzeini.-Forsch. 24:1649 (1974).

Res.) 5.

M.,

pharmacokinetics

amide

Nueten, Fontaine, novel type

Michiels,

Ortho

Raritan,

J.: Loperamide of antidiarrheai

creasing

Van

24:1633

Capsules,

Corporation,

J.,

rats

unwas

particular

Re8.)

Imodium

Pharmaceutical

References I.

(Drug

(1974).

1 per

in the urine as after seven days was

Arzeim.-Forsch.

physiologic

approximately

FULLER

Brugmans, novel type

also

independent

AND

and

maximum were

safety

Excretion

cent of changed

syrup

concentration-versusthat the two formu-

availability. The serum concentrations lation.

the

comparable

have

indicating

for

WEINTRAUB,

D.: In Research.

Britain,

‘l’he Journal

Vol. 1. ReproNational InstiMd., 1972.

Wagner, Making

J. 0.: Pharma-

Program. University Arbor, Mich., 1974. Practical Statistics for Methuen, Norwich,

1969.

of

Clinical

Pharmacology