Interaction
`Cimetidine,
`
`With
`of Diazepam
`Two H2-Receptor
`
`Famotidine
`Antagonists
`
`and
`
`Ann
`
`Locnislcar,
`Michael
`
`David
`A.
`Zinny,
`
`J. Greenblatt,
`MD,
`
`and
`
`MD,
`Richard
`
`Jerold
`FCP,
`I. Shader,
`
`S. Harmatz,
`MD
`
`under
`Eleven
`antagonist.
`healthy
`as an H2-receptor
`investigation
`intravenous
`three
`dose
`occasions:
`on
`of diazepam
`a single
`10 mg
`once
`during
`bid,
`40 mg
`of
`famotidine
`coadministration
`once
`other
`without
`drug
`treatment
`(control).
`Multiple
`the
`days
`after
`each
`diazepam
`dose.
`Diazepam
`seven
`were
`electron
`capture
`concentrations
`measured
`three
`treatment
`differences
`the
`no
`significant
`volume
`volume
`of
`compartment
`distribution.
`diazepam
`the
`control
`with
`elimination
`(72 vs 55 hr. P < .05),
`the
`under
`curve
`(AUC)
`P < .05),
`and
`total
`(0.20
`vs
`reduced
`0.28
`increased
`vs
`A[JC
`for
`desmethyldiazepam
`also
`(4.6
`3.8
`no
`differences
`there
`were
`significant
`famotidine
`between
`(53 vs 55 hr),
`total AUG
`half-life
`in diazepam
`elimination
`clearance
`(0.28
`vs 0.28 mL/min/kg)
`in seven-day
`AUG
`for
`3.8
`cimetidine
`hr-i2g/mL).
`Thus,
`therapeutic
`of
`signifi-
`and
`of
`of diazepam
`desmethyldiazepam.
`Therapeutic
`doses
`that
`diazepam
`desmethyldiaze
`pain
`kinetics,
`suggesting
`adminis-
`are
`interaction
`when
`diazepam
`and
`famotidine
`practice.
`
`of
`
`blood
`and
`gas
`
`by
`among
`total
`or
`treatment,
`total
`area
`clearance
`
`or
`doses
`
`is currently
`Famotidine
`received
`male
`volunteers
`once
`during
`coadministration
`and
`300 mg qid,
`cimetidine
`during
`were
`drawn
`samples
`plasma
`desmethyldiazepam
`There
`were
`chromatography.
`diazepam
`in
`central
`conditions
`the
`During
`cimetidine
`compared
`significantly
`increased
`was
`half-life
`hr-ig/mL,
`(11.8
`vs
`9.8
`increased
`P < .05).
`Seven-day
`mL/min/kg,
`P < .05). However,
`hr-ig/mL,
`treatment
`conditions
`and
`control
`(9.5 vs 9.8 hr-ig/mL),
`or
`total
`desmethyldiazepam
`(3.9
`vs
`the
`cantly
`impair
`clearance
`not
`do
`famotidine
`impair
`is no significant
`there
`kinetic
`tered
`concurrently
`in clinical
`
`as
`
`and
`
`C imetidine,
`
`antagonist,
`H2-receptor
`an
`of
`property
`pharmacologic
`additional
`oxidizing
`capacity.13
`hepatic
`microsomal
`drug
`number
`of
`drugs
`coadministered
`a
`biotransformed
`oxidative
`processes,
`
`with
`by
`
`the
`
`has
`impairing
`When
`are
`
`that
`cimetidine
`
`(Ms.
`
`Mr.
`Locniskar,
`Pharmacology
`of Clinical
`From the Division
`of
`Departments
`and
`Shader).
`Harmatz,
`and Drs. Greenblatt
`of Medicine
`University
`School
`Psychiatry
`and Medicine,
`and
`Tufts
`and Technical
`Boston;
`and Medical
`New England Medical Center,
`and Boston.
`(Dr.
`Zinny),
`Needham
`Research
`Associates,
`Inc.
`in part
`by grant MI-$-34223
`Massacusetts.
`Supported
`from
`the
`United
`States
`Public Health
`Service
`and by a grant-in-aid
`from
`Merck
`Sharp
`and
`Dohme
`Research
`Laboratories.
`Address
`for
`MD, FCP, Division
`of Clinical
`Phar-
`reprints:
`David
`J. Greenblatt,
`macology,
`Box
`Tufts-New
`England Medical
`Center,
`171
`1007,
`Harrison
`Avenue.
`Boston, MA 02111.
`Received:
`December
`22, 1985.
`Accepted:
`January
`20, 1986.
`
`metabolic
`half-iife,
`
`and
`
`leading
`clearance,
`impairs
`area
`under
`increased
`elimination
`higher
`curve,
`concentration-time
`dosing.1-9
`multiple
`during
`concentrations
`an
`is not
`capacity
`oxidizing
`tion
`of
`drug
`action
`of H2
`antagonists,
`of
`the
`component
`share
`this
`oxidative
`does
`not
`ranitidine
`a
`(MK-208)
`is
`Famotidine
`property.10’11
`is under
`investigation
`receptor
`antagonist
`that
`disease.12
`Since
`treatment
`of peptic
`ulcer
`administration
`of H2
`antagonists
`with
`other
`tions
`is common,
`evaluation
`of
`possible
`the
`al-inhibiting
`properties
`of new
`drugs
`of
`considerable
`importance.
`The
`present
`ed
`the
`influence
`of
`famotidine
`on
`the
`ics
`of
`a
`single
`intravenous
`dose
`healthy
`volunteers.
`The
`effect
`of
`epam
`kinetics
`was
`compared
`with
`of
`cimetidine
`to impair
`diazepam
`
`to
`
`increased
`the
`plasma
`steady-state
`This
`inhibi-
`invariable
`since
`inhibition
`new
`
`H2-
`the
`
`for
`concurrent
`medica-
`microsom-
`class
`is of
`this
`evaluat-
`study
`pharmacokinet-
`in
`of
`diazepam
`diaz-
`famotidine
`on
`the
`known
`capacity
`clearance.
`
`J ClIn Pharmacol
`
`1986;26:299-303
`
`299
`
`1
`
`TEVA1080
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`
`

`

`LOCNISKAR
`
`ET AL
`
`METHODS
`
`Subjects
`
`volunteers,
`male
`Healthy
`after
`giving
`written
`pated
`active,
`ambulatory
`healthy,
`disease,
`and
`of medical
`other
`medication.
`Twelve
`and
`completed
`all
`three
`11
`
`partici-
`19 to 49 years,
`aged
`All were
`informed
`consent.
`evidence
`adults
`without
`none
`were
`receiving
`any
`volunteers
`began
`the
`study,
`trials.
`
`Protocol
`
`described
`methods
`modifications.
`(Ro 7-9957)
`calibration
`alcohol
`was
`in
`the
`
`onto
`
`detail
`addition
`standard,
`were
`extracted
`following
`evaporated
`alcohol
`using
`was
`
`previously,13-16
`in
`using
`phy
`of
`a diaze-
`After
`minor
`with
`plasma
`internal
`as
`pam analogue
`into
`standards
`samples
`and
`which
`(98.5:1.5),
`benzene:isoamyl
`to dry-
`separated,
`extract
`the
`organic
`(85:15),
`toluene:isoamyl
`ness,
`reconstituted
`auto-
`an
`chromatograph
`and
`injected
`a Model
`used
`instrument
`The
`matic
`sampler.
`(Avondale,
`gas
`chromatograph
`Packard
`5840A
`Hewlett
`detector.
`with
`a 15 mCi
`electron-capture
`PA)
`equipped
`X 4 mm
`length
`was
`coiled
`glass,
`4 ft
`in
`The
`column
`80/100
`on
`internal
`diameter,
`packed
`with
`3% SP-2250
`Supelcoport
`(Supelco
`Inc.,
`Bellefonte,
`PA). Operating
`parameters
`were:
`carrier
`gas,
`argon:methane
`(95:5);
`flow rate,
`30 mL/min;
`injection
`and
`detector
`tempera-
`tures,
`310#{176}C;and
`column
`temperature,
`265#{176}C.All
`samples
`from a given
`subject’s
`set
`of
`trials
`were
`extracted
`and
`analyzed
`on
`same
`using
`the
`same
`calibration
`standards.
`cimetidine
`prescribed
`Compliance
`with
`the
`by measurement
`verified
`famotidine
`regimens
`was
`before
`plasma
`concentrations
`in samples
`drawn
`120,
`144,
`96,
`epam
`dosage
`and
`at 24,
`48,
`72,
`using
`hours.
`Analyses
`were
`performed
`diazepam
`remaining
`following
`analysis
`of
`All
`samples
`methyldiazepam
`concentrations.
`before
`drawn
`being
`“trough”
`sented
`the
`condition,
`Cimetid-
`or
`famotidine.
`doses
`day’s
`first
`of cimetidine
`high-perfor-
`determined
`by
`me
`concentrations
`were
`as
`described
`(HPLC)
`mance
`liquid
`chromatography
`were
`also measured
`previously.5
`Famotidine
`levels
`of plasma
`samples
`HPLC17
`following
`extraction
`mt., Harbor
`Baker-b
`system
`(Analytichem
`One
`milliliter
`of methanol,
`1 mL
`of water,
`were
`successively
`plasma,
`and
`5 mL
`of water
`through
`a 2.8-mL
`silica
`cartridge.
`Two
`milliliters
`acetonitrile
`was
`then
`added;
`the
`eluate
`was
`collected
`and
`evaporated
`to dryness
`under
`nitrogen.
`Two
`hun-
`dred
`microliters
`of 0.17 N acetic
`acid
`was
`then
`added
`and
`the
`tubes
`sonicated
`for
`five minutes.
`The
`samples
`were
`then
`centrifuged
`and
`the
`supernatant
`trans-
`iL
`ferred
`to
`autosampling
`vials,
`of which
`150
`was
`injected.
`A Waters
`HPLC
`system
`(Millipore,
`Milford,
`MA)
`was
`consisting
`of
`a Waters
`ultraviolet
`absorbance
`detector,
`3-cm
`Brownlee
`RP-8
`guard
`column
`(Brownlee
`Santa
`Clara,
`CA)
`and
`a
`25-cm
`5-Mm
`Altex
`analytical
`column
`(Altex
`Scientific,
`Berkeley,
`The
`detector
`was
`at 267
`nm.
`The mobile
`phase
`0.019 M phosphoric
`acid:acetonitrile
`(90:10)
`at
`rate
`of 1.0 mL/min.
`
`three
`day
`
`the
`
`703
`used,
`
`a
`
`Labs,
`RP-8
`CA).
`was
`a flow
`
`or
`of
`diaz-
`168
`and
`plasma
`and
`des-
`repre-
`the
`
`by
`a
`
`with
`CA).
`City,
`1 mL
`of
`run
`of
`
`480
`
`set
`
`three-way,
`single-dose,
`a
`in
`single
`10-mg
`a
`occasion,
`each
`given.
`The
`three
`was
`diazepam
`follows:
`(1) diazepam
`as
`were
`concurrent
`treatment
`with
`24
`beginning
`hours
`before
`continuing
`and
`for
`the
`diazepam
`the
`pharmaco-
`of
`intravenously
`given
`during
`cimetidine
`300 mg
`qid,
`diazepam
`administration
`seven-day
`duration
`study;
`(3) diaze-
`control
`without
`
`in the
`
`and
`state,
`
`of
`
`participated
`Subjects
`trial.
`On
`crossover
`dose
`of
`intravenous
`modes
`of administration
`during
`given
`intravenously
`bid,
`famotidine
`40 mg
`diazepam
`administration
`entire
`seven-day
`duration
`kinetic
`study;
`(2) diazepam
`with
`concurrent
`treatment
`before
`beginning
`24
`hours
`the
`entire
`and
`continuing
`for
`the
`diazepam
`pharmacokinetic
`pam
`given
`intravenously
`drug
`coadministration.
`elapsed
`At
`least
`three
`diazepam.
`of
`three
`administrations
`randomized.
`was
`the
`three
`trials
`(2 mL
`of diazepam
`trial,
`10 mg
`For
`each
`diazepam
`Injecta-
`available
`preparation
`of
`the
`commercially
`was
`Laboratories],
`5 mg/mL)
`Valium
`[Roche
`a period
`antecubital
`vein
`over
`directly
`into
`were
`Venous
`blood
`samples
`30
`seconds.
`to
`(Becton
`Vacutainer
`tubes
`into
`heparinized
`admin-
`before
`diazepam
`NJ)
`Rutherford,
`1, 2, 4, 6, 8,
`30 minutes
`and
`and
`at 5, 15,
`following
`144,
`and
`168
`hours
`96,
`120,
`centri-
`blood
`samples
`were
`Venous
`until
`and
`was
`separated
`frozen
`plasma
`the
`four
`for
`before
`assay.
`Subjects
`fasted
`and
`each
`diazepam
`administration.
`Following
`a normal
`unrestricted
`diet
`resumed.
`
`weeks
`
`between
`The
`
`of
`
`each
`sequence
`
`the
`of
`
`an
`
`of
`ble
`infused
`of
`15
`drawn
`Dickinson,
`and
`istration
`48,
`12,
`24,
`administration.
`fuged,
`and
`the
`time
`of
`hours
`after
`this
`period,
`
`72,
`
`was
`
`Analysis
`
`of Plasma
`
`Concentrations
`
`of diazepam
`Concentrations
`in
`all
`desmethyldiazepam,
`termined
`by electron-capture
`
`its maj or metabolite,
`and
`samples
`were
`plasma
`gas-liquid
`chromatogra-
`
`de-
`
`300
`
`#{149}J COn Pharmacol
`
`1986;26:299-303
`
`2
`
`

`

`INTERACTION
`
`OF DIAZEPAM
`
`AND
`
`H2 ANTAGONISTS
`
`Kinetic
`
`and
`
`Statistical
`
`Analyses
`
`Figure
`
`representative
`
`1 shows
`0.92.
`exceeded
`always
`curves.
`concentration-time
`plasma
`summarized
`are
`variables
`Kinetic
`amOng
`differences
`were
`no significant
`(control,
`cimetidine,
`ment
`conditions
`in diazepam
`V1 (0.26,0.24,
`respectively)
`1.16,
`and
`Values
`or Vd
`(1.17,
`L/kg).
`are
`consistent
`with
`previously
`this
`study
`healthy
`male
`volunteers.10’23-27
`values
`in
`overall
`differences
`were
`observed
`among
`treatment
`conditions
`in diazepam
`t112 (55,
`hr),
`total
`clearance
`(0.275,
`0.201,
`and
`0.277
`
`1.08
`
`I. There
`in Table
`treat-
`the
`three
`and
`famotidine,
`and
`0.21 L/kg)
`observed
`reported
`Significant
`the
`three
`72,
`and
`53
`mL/min/
`
`in
`
`+I
`
`Days After Dtazeam
`
`Dose
`
`concentrations
`1. Plasma
`in a representative
`during
`coadministration
`
`of diazepam
`subject
`in the
`of cimetidine
`
`and
`control
`or
`
`desmeth-
`condi-
`famotid-
`
`Figure
`yldiazepam
`and
`tion
`me.
`
`as
`were
`
`Plasma
`iterative
`niques
`points
`exponential
`the
`function
`following
`apparent
`total
`(Vd),
`plasma
`infinity
`the
`curve
`dosage
`For
`among
`analysis
`sures.
`among
`ences
`between
`assessed
`
`three
`
`t
`
`analyzed
`are
`concentrations
`diazepam
`regression
`least
`squares
`nonlinear
`elsewhere:’8’19
`in
`detail
`described
`sum
`of
`a
`linear
`to
`fitted
`two
`and
`exponents
`terms.2#{176}Coefficients
`used
`to determine
`of best
`fit21 were
`pharmacokinetic
`variables
`for
`diazepam22:
`the
`volume
`of
`central
`compartment
`(V1),
`of
`distribution
`using
`the
`area
`method
`volume
`half-life
`(t112),
`area
`under
`the
`elimination
`total
`concentration-time
`curve
`time
`zero
`to
`from
`total
`(AUC),
`and
`clearance.
`area
`under
`The
`plasma
`desmethyldiazepam
`concentration-time
`168
`from
`time
`0 through
`hours
`after
`diazepam
`the
`by
`was
`determined
`trapezoidal
`method.
`variable,
`each
`kinetic
`overall
`differences
`groups
`the
`three
`treatment
`were
`assessed
`with
`of
`variance
`(ANOVA)
`repeated
`When
`significant
`differences
`were
`the
`treatment
`groups,
`individual
`between
`control
`and
`cimetidine
`treatments
`control
`and
`famotidine
`treatments
`by Dunnett’s
`test.
`
`by
`tech-
`Data
`three
`from
`the
`
`or
`
`by
`mea-
`found
`differ-
`and
`were
`
`RESULTS
`
`cases,
`In all
`consistent
`was
`exponential
`
`disappearance
`with
`the
`terms.
`The
`
`of diazepam
`linear
`sum
`goodness-of-fit
`
`of
`
`from
`two
`parameter
`
`plasma
`or
`three
`(R2)
`
`Effect
`
`of Famotidlne
`
`and Clmetldine
`
`on the Kinetics
`
`of Diazepam
`
`and Desmethyldiazepam
`
`TABLE
`
`I
`
`Trial C
`(Control)
`
`B
`Trial
`(Cimetidine)
`
`A
`Trial
`(Famotidine)
`
`of F*
`Value
`(ANOVA)
`
`Control
`Cimetidine
`
`vs
`
`Control
`Famotidine
`
`vs
`
`Dunnett’s
`
`tTest
`
`Diazepam
`V1 (L/kg)
`Vd (L/kg)
`t(hr)
`AUC (hr-g/mL)
`Total
`CL (mL/min/kg)
`Desmethyldlazepam
`7-Day
`AUC
`(hr-g/mL)
`
`0.26
`1.17
`54.7
`9.78
`0.275
`
`0.04t
`±
`0.11
`±
`6.5
`±
`± 1.24
`± 0.042
`
`0.24
`1.16
`72.2
`11.76
`0.201
`
`± 0.02
`± 0.11
`9.6
`±
`± 0.93
`0.016
`±
`
`0.21
`1.08
`52.6
`9.45
`0.277
`
`± 0.02
`0.11
`±
`7.7
`±
`± 1.20
`± 0.035
`
`(NS)
`0.88
`(NS)
`0.89
`14.18(P<.001)
`8.62
`(P<
`7.62
`
`(P
`
`<
`
`.005)
`.005)
`
`P<.05
`
`P<
`P <
`
`.05
`.05
`
`3.84
`
`± 0.24
`
`4.58
`
`± 0.33
`
`3.93 ± 0.23
`
`5.09 (P
`
`< .02)
`
`P <
`
`.05
`
`of
`
`freedom
`5Degrees
`V, =
`of
`the
`volume
`ANOVA
`analysis
`
`=
`
`tvalues
`2,20;
`compartment;
`central
`of variance.
`
`are mean
`Vd
`
`error.
`standard
`±
`volume
`of distribution;
`
`CL
`
`clearance;
`
`AUG
`
`area
`
`under
`
`the plasma
`
`concentration-time
`
`curve;
`
`CLINICAL
`
`RESEARCH:
`
`CNS DRUGS
`
`NS
`NS
`NS
`
`NS
`
`301
`
`3
`
`

`

`LOCNISKAR
`
`ET AL
`
`TABLE
`
`II
`
`Plasma
`
`Concentrations
`Famotldine
`
`of Cimetidine
`
`and
`
`Plasma
`
`ConcentratlOn*
`
`Time
`Diazepam
`
`After
`Dose (hr)
`
`Predose
`24
`48
`72
`96
`120
`144
`168
`
`Cimetldine
`(sig/mL)
`
`0.16
`0.14
`0.14
`0.22
`0.14
`0.11
`0.13
`0.11
`
`± 0.04
`± 0.04
`± 0.04
`± 0.02
`± 0.04
`±
`0.03
`± 0.04
`±
`0.06
`
`Famotldlne
`(ng/mL)
`
`26
`26
`32
`21
`23
`32
`33
`34
`
`±
`± 4
`±
`10
`± 3
`5
`±
`±
`10
`8
`±
`±
`13
`
`*Mean
`
`± standard
`
`err’
`
`oft
`
`he mean.
`
`diazepam
`control
`
`of
`the
`in
`famotidine
`
`or
`
`With
`Famotidine
`
`Control
`
`Wilt
`Chnetidln,
`
`140
`
`120
`
`too
`
`80
`
`80
`
`40
`
`20
`
`.9
`
`:aE
`
`I,
`
`2.
`
`Figure
`elimination
`condition
`cimetidine.
`
`Individual
`half-life
`and
`during
`See
`Table
`
`mean
`and
`total
`and
`coadminist
`for
`statistical
`
`I
`
`values
`
`(± SE)
`clearance
`of
`ration
`analysis.
`
`and
`
`11.76,
`
`and
`overall
`
`is
`
`total
`were
`
`AUC
`also
`AUG
`
`did
`the
`
`hr-g/mL).
`9.45
`in
`differences
`and
`(3.84,
`4.58,
`any
`not
`indicate
`control
`drug-free
`coadministration
`t#{189} was
`significantly
`total
`increased,
`and
`during
`cimetidine
`control
`(Ta-
`with
`desmethyldiaze-
`the
`cimetidine
`in
`with
`the
`control
`
`the
`
`for
`
`This
`compound.7’8
`parent
`the
`from
`formed
`it
`once
`and
`desmethyl-
`of diazepam
`of clearance
`impairment
`lead
`to increased
`caused
`by cimetidine
`will
`diazepam
`compounds
`dur-
`concentrations
`of
`these
`two
`plasma
`if cimetidine
`ing
`chronic
`treatment
`with
`diazepam
`coadministered.4’5
`contrast,
`famotidine
`treatment
`In
`any
`did
`not
`have
`significant
`influence
`any
`of
`on
`kinetic
`parameters
`for diazepam
`and
`desmethyldiaze-
`pam.
`This
`is consistent
`with
`reports
`earlier
`indicating
`that
`famotidine
`does
`not
`microsomal
`drug
`inhibit
`suggests
`that
`famotidine
`administra-
`oxidation,28
`and
`tion
`to
`diazepam-treated
`patients
`would
`have
`significant
`effect
`on
`steady-state
`concentrations
`diazepam
`and
`its major
`metabolite.
`
`is
`
`the
`
`no
`of
`
`as
`
`(9.78,
`kg),
`significant
`There
`desmethyldiazepam
`seven-day
`t
`test
`Dunnett’s
`3.93
`hr-ig/mL).
`difference
`between
`significant
`and
`famotidine
`trial
`condition
`the
`condition.
`However,
`diazepam
`prolonged,
`AUG
`significantly
`clearance
`significantly
`reduced
`as
`compared
`coadministration
`trial
`ble
`I, Figure
`2). Likewise,
`AUG
`pam
`was
`significantly
`increased
`treatment
`condition
`compared
`condition.
`Plasma
`shown
`with
`
`are
`ance
`
`and
`cimetidine
`II and
`in Table
`the
`prescribed
`
`famotidine
`indicate
`regimens.
`
`concentrations
`acceptable
`compli-
`
`for
`grateful
`are
`We
`and
`Technical
`Research
`MA.
`
`the
`
`assistance
`Associates,
`
`staff
`
`the
`of
`Needham
`
`of Medical
`and
`Boston,
`
`DISCUSSION
`
`REFERENCES
`
`the
`and
`
`three-way.
`single-dose,
`randomized
`present
`The
`two H2-receptor
`effect
`of
`assessed
`study
`crossover
`on
`the
`phar-
`famotidine,
`cimetidine
`antagonists,
`volunteers.
`male
`in healthy
`of diazepam
`macokinetics
`coadministration
`with
`previous
`Consistent
`reports,4-6
`(300
`of cimetidine
`doses
`of
`recommended
`therapeutic
`prolongation
`of diaze-
`mg
`qid)
`resulted
`in significant
`and
`reduction
`of
`total
`pam
`increase
`in the AUC,
`t#{189},
`increase
`in the AUG
`for
`clearance.
`There
`was
`also
`an
`impairment
`of meta-
`desmethyldiazepam,
`suggesting
`bolic
`clearance
`the maj or metabolite
`of diazepam,
`
`of
`
`302
`
`#{149}J COn Pharmacol
`
`1986;26:299-303
`
`A, Gugler
`1. Somogyi
`din
`Pharmacokinet
`
`R: Drug
`1982;7:23-41.
`
`interactions
`
`with
`
`cimetidine.
`
`Cimetidine-drug
`
`interactions.
`
`Am
`
`f Med
`
`J: Cimetidine-benzodia.
`JF, Segal
`J Hosp
`1981;38:1365-
`Pharm
`Am
`
`AJ:
`2. Sedman
`1984;76:109-114.
`3. Ruffalo
`RL, Thompson
`zepine
`drug
`interaction.
`1366.
`4. Klotz
`levels
`517.
`5. Greenblatt
`
`U, Reiman
`cimetidine.
`
`by
`
`of
`I: Elevation
`dim
`Pharmacol
`
`steady-state
`Ther
`
`diazepam
`1981;30:513-
`
`DJ, Abernethy
`
`DR. Morse
`
`DS,
`
`et
`
`al: Clinical
`
`4
`
`

`

`INTERACTION
`
`OF DIAZEPAM
`
`AND
`
`H2 ANTAGONISTS
`
`of diazepam
`
`and
`
`cimetidine.
`
`DJ, Divoll M,
`drug
`oxidation
`(acetaminophen
`toxicity
`
`et al: Differen-
`(antipyrine
`and
`and
`braze-
`by cimetidine.
`
`J
`
`of
`
`cimetidine
`and
`
`on
`oxazepam.
`
`the
`
`in
`
`et al:
`
`al:
`et
`metab-
`and
`bra-
`
`Inhibition
`al:
`not
`ranitidine.
`
`of
`
`al: Famotid-
`et
`MS.
`H2-receptor
`antag-
`ranitidine
`in
`the
`Gastroenterology
`
`anal-
`
`dIm
`
`interaction
`the
`of
`importance
`I Med
`N Engl
`1984;310:1639-1643.
`DR, Greenblatt
`6. Abernethy
`cimetidine
`on
`of
`tial
`effect
`versus
`conjugation
`diazepam)
`pam):
`Prevention
`of acetaminophen
`Ther
`1983;224:508-513.
`Pharmacol
`Exp
`7. Klotz
`U, Reimann
`I:
`Influence
`pharmacokinetics
`of
`desmethyldiazepam
`J dim Pharmacol
`1980;18:517-520.
`Eur
`DR. et al: Cimetidine
`8. Divoll M, Greenblatt
`DJ, Abernethy
`desmethyldiazepam
`impairs
`clearance
`of antipyrine
`and
`J Am
`the
`elderly.
`1982;30:684-689.
`Ger
`Soc
`Interaction
`9. Abernethy
`DR, Greenblatt
`DJ, Divoll M,
`alprazolam
`of cimetidine
`with
`the
`triazobo
`benzodiazepines
`and
`triazolam.
`1983;80:275-278.
`Psychopharmacology
`DJ,
`10. Abernethy
`DR.
`Greenblatt
`Eshelman
`FN,
`does
`Ranitidine
`not
`impair
`oxidative
`or conjugative
`olism: Noninteraction
`with
`antipyrine,
`diazepam,
`zepam.
`1984;35:188-192.
`dim
`Pharmacol
`Ther
`JF, Wargin WA,
`11.
`Powell
`JR, Rogers
`et
`theophybline
`clearance
`by
`cimetidine
`but
`Med
`1984;144:484-486.
`Arch
`Intern
`Collen
`12. Howard
`JM, Chremos
`AN,
`histamine
`me,
`a new,
`potent,
`long-acting
`and
`onist:
`Comparison
`with
`cimetidine
`treatment
`of Zollinger-Ellison
`syndrome.
`1985;88:1026-1033.
`chromatographic
`gas
`DJ: Simultaneous
`13. Greenblatt
`metabolite,
`desmethyldiaze-
`and
`its major
`ysis
`for
`diazepam
`of
`double
`internal
`standardization.
`pam,
`with
`use
`Chem
`1978;24:1838-1841.
`DJ, Ochs
`14. Greenblatt
`its major
`and
`metabolite
`1980;70:89-93.
`pharmacology
`RI: Benzodiazepines:
`15. Greenblatt
`DJ, Shader
`V (eds):
`techniques,
`in Richens
`A, Marks
`Therapeutic
`Monitoring.
`Edinburgh,
`UK,
`Churchill
`Livingston,
`272-280.
`16. Greenblatt
`capture
`gas-liquid
`
`HR.
`into
`
`BL: Entry
`Lloyd
`cerebrospmnal
`
`of diazepam
`Psycho-
`fluid.
`
`Analytic
`Drug
`1981;
`
`of benzodiazepines
`Dl: Analysis
`chromatography,
`in Sunshine
`
`by electron-
`I, Jatbow
`
`P1
`
`for
`
`Toxicology,
`
`vol
`
`2. Boca
`
`and
`
`H2
`
`et al: Pharmacoki-
`HR,
`HJ, Ochs
`DJ, Pfeifer
`intravenous,
`intramus-
`in humans
`after
`J Pharmacol
`administration.
`Exp
`Ther
`
`RI, Franke
`of
`intravenous,
`J Pharmaceutical
`
`K, et al: Pharmacoki-
`and
`intramuscular
`1979;68:57-
`Sd
`
`(ed):
`
`Program
`Software.
`Statistical
`Regression.
`Berkeley,
`Uni-
`
`RM:
`S, Elashoff
`I Pharmacolcinet
`
`Statistical
`Bio-
`
`pharmacokinet-
`
`et
`
`al: Diazepam
`1980;
`Ther
`
`Greenblatt
`HR,
`relation
`to
`
`in
`
`DJ, Divoll
`and
`sex.
`
`age
`
`al: Diazepam
`et
`M,
`1981;
`Pharmacology
`
`(eds): Methodology
`Analytical
`Press,
`Raton,
`FL CRC
`1982;
`19-24.
`et al: Analyti-
`GA,
`17. Vincek
`WC, Constanzer
`ML, Hessey
`famotidine,
`an
`cal method
`for
`the
`quantification
`of
`J
`receptor
`blocker
`in
`plasma
`urine.
`dhromatogr
`1985;338:438-443.
`18. Greenblatt
`netics
`of quinidine
`cular
`and
`oral
`1977;202:365-378.
`Dj, Shader
`19. Greenblatt
`bioavailability
`netics
`and
`oral
`borazepam
`in humans.
`63.
`WJ
`20. Dixon
`BMDP
`Nonlinear
`AR: Derivative-Free
`Press,
`1981.
`versity
`of California
`HG, Riegelman
`21. Boxenbaum
`pharmacokinetics.
`in
`estimations
`1974;2:123-148.
`pharm
`J: Clinical
`22. Greenblatt
`DJ, Koch-Weser
`J Med
`964-970.
`ics. N EngI
`1975;293:702-705,
`JS,
`23. Greenblatt
`DJ, Allen
`MD,
`Harmatz
`disposition
`determinants.
`dim
`Pharmacol
`27:301-312.
`24. Ochs
`kinetics
`23:24-30.
`DJ, Divoll
`DR. Greenblatt
`25. Abernethy
`clearance
`and
`distribution
`tions
`in
`drug
`1981;217:681-685.
`Exp
`Ther
`Pharmacol
`DJ, Ochs
`M, Greenblatt
`26. Divoll
`intramuscular
`and
`of oral
`bioavailability
`1983;62:1-8.
`sex. Anesth
`of
`age
`and
`Analg
`MA,
`A, Greenbbatt
`DJ, Zinny
`27. Locniskar
`antacid
`of
`and
`effect
`food
`and
`bioavailability
`from a slow release
`preparation.
`absorption
`1984;24:255-263.
`col
`P, Rosenkranz
`28. Kbotz
`U, Arvela
`does
`not
`H-2
`receptor
`antagonist,
`secretion
`of
`diazepam
`or
`tubular
`1985;28:671-675.
`dim
`Pharmacol
`
`M,
`due
`
`et
`to
`
`al: Altera-
`obesity.
`
`HR.
`
`al: Absolute
`et
`diazepam:
`Effects
`
`et
`
`ab: Absolute
`on
`diazepam
`I dim
`Pharma-
`
`B: Famotidine,
`affect
`hepatic
`of
`procainamide.
`
`a new
`elimination
`Eur
`
`I
`
`I
`
`CLINICAL
`
`RESEARCH:
`
`CNS DRUGS
`
`303
`
`5
`
`

`

`April 1986
`vol. 26 No.4
`
`Official Publication of the American College of Clinical Pharmacology
`'his
`journal
`is indexed in Index Medicus, Excerpta Medica, and Current Contents.
`
`Submissions:
`Medicine,
`
`John C. Samberg. MD, Editor, Journal of Clinical Pharmacology,
`1300 Morris Park Avenue. Bronx, NY 10461.
`
`Albert Einstein College of
`
`JOHN C. SOMBERG Editor
`DEBORAH L. KEEFE Associate Editor
`E. HUTCHEON
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`DUNCAN
`l-IAROLD R. DETrELBACH Associate Editor for Therapeutic Reviews
`
`EDITORIAL
`BOARD
`EDITORS
`SECTION
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`HAROLD C. NEU New York, NY;
`CYNTIIIA ALTMAN Philadelphia, PA
`Antimicrobial Agents
`KEIKO AOGAICHI Nutley, NT
`ANDREW WHELTON Baltimore, MD:
`JOSEPH R. BIANCHINE Nutley, NT
`Renal Drugs
`GERALD J. YAKATAN Morris Plains. NJ:
`JAMES BLANCHARD Tucson, AZ
`GILBERTJ. BURCKARTPittsburgh, PA
`Pharmacokinetics
`'BETH MAGGIO CAVAUERE Kansas City, MO: EDWARD R. BURNS Bronx, NY
`Book Reviews
`BENJAMlN CALESNICKPhiladelphia. PA
`STEWART EHRREICH Rockville, MD
`PETER H. WIERNIK Bronx, NY;
`Oncology
`WALTER F1.AMENBAUM New York, NY
`DAVID J. GREENBLATT Boston. MA
`DENNIS MIURA Bronx. NY;
`Brief Reports
`JR Los Angeles. CA
`HENRY GONG,
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`JR Valhalla. NY
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`
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`Clinical Pharmacology.
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`The Journal of Clinical Pharmacology
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`• April 1986 • C
`
`6
`
`

`

`
`
`The Regulatory Process
`
`The Canadian Drug Regulatory Process
`
`
`Pharmacokinetlc and Biopharmaceutlc Principles
`for Clinical Pharmacologists
`——__.___.________
`
`Controversy I: Patients or Healthy Volunteers for
`Pharmacokinetlc Studies?
`—_____._._______
`
`Rising Multiple-Dose Pharmacokinetics of
`Labetaloi In Hypertensive Patients
`;—___.___________
`Dose- and Time-Dependent Binding and Kinetics
`of Pindoloi in Patients With Congestive Heart
`Failure
`__-_.___._._________
`
`The Influence of Pindoiol and
`Hydrochlorothlazide on Blood Pressure and
`Plasma Renin and Plasma Lipid Levels
`‘—______________
`
`Pharmacoitinetics of Captoprll in Elderly Healthy
`Male Volunteers
`
`
`The Effect of Etodolac Administration on Renal
`Function In Patients With Arthritis
`
`
`intravenous Dezocine for Postoperative Pain:
`A Double-Blind, Placebo-Controlled Comparison
`With Morphine—____,__________
`
`Absence of Tachyphylaxls in Gastric Acid
`Secretion During Pentagastrin infusion
`—._______________
`
`Pharmacokinetlcs of Ranitidlne in Patients With
`Renal Failure
`
`Pharmacokinetics and Clinical Efiects of
`Alprazolam Following Single and Multiple Oral
`Doses in Patients With Panic Disorder
`
`
`interaction of Diazepam With Famotidine and
`
`Clrnetidine. Two Hz-Receptor Antagonists
`
`Noninteractlon of Digoxln and Niiedlpine in
`Cardiac Patients
`
`
`COMPLETE CONTENTS ON PAGE 0
`h——.____—____
`
`7
`
`