`Ths
`JOURNAL
`OF
`PHARMAcOLOGY
`Oopyright
`C 1979
`by The American
`
`AND
`Society
`
`EXPERIMENTAL
`for Pharmacology
`
`THERAPEUTICS
`and Experimental
`
`TherapeutiCS
`
`VoL 208, No.2
`Printed
`in USA.
`
`Pharmacokinetics
`
`of Naloxone
`
`and Naltrexone
`
`in the
`
`2
`
`NATHAN
`
`LEON
`
`PACE,
`
`ROB
`
`G.
`
`PARRISH,
`
`MICHAEL
`
`M.
`
`LiEBERMAN,
`
`K. C. WONG
`
`AND
`
`RICHARD
`
`A. BLATNICK
`
`Department
`Army
`Medical
`
`of Anesthesiology,
`Center,
`Fort
`
`University
`Sam Houston,
`
`of Utah College
`Texas
`(R.G.P.
`
`of Medicine,
`, M.M.L.)
`
`Accepted
`
`for publication
`
`September
`
`25,
`
`1978
`
`Salt
`
`Lake
`
`City,
`
`Utah
`
`(N.L.P.,
`
`K.C. W., R.A.B.),
`
`and
`
`the Clinical
`
`Investigation
`
`Service.
`
`Brooke
`
`Downloaded from
`
`ABSTRACT
`Pace,
`Nathan
`K. C. Wong,
`naloxone
`and
`208:
`254-256,
`
`Rob
`Leon,
`Richard
`and
`naltrexone
`1979.
`
`G. Parrish,
`A. Blatnick:
`in the
`dog.
`
`Lieberman,
`M.
`Michael
`Pharmacokinetics
`J. Pharmacoi.
`Exp.
`
`of
`Ther.
`
`The
`were
`
`serum
`studied
`
`kinetics
`in each
`
`of 5 mg/kg
`of
`groups
`two
`
`of
`
`i. v. naloxone
`offive
`dogs;
`
`or naltrexone
`serum
`samples
`
`Serum
`
`from 2 mm to
`obtained
`were
`were
`determined
`centrations
`naioxone
`and
`levels
`of both
`elimination
`life during
`the
`± SE.)
`for naloxone
`and
`and
`naltrexone.
`Although
`human
`naloxone,
`naltrexone
`is
`long-acting
`dissipated
`in the
`dog.
`
`±
`
`con-
`injection.
`after
`2 hr
`Serum
`radioimmunoassay.
`by
`half-
`serum
`fell
`rapidly;
`naltrexone
`71 .2
`±
`8.9 mm (mean
`phase
`was
`85.1
`9.0 mm (mean
`± S.E.)
`for
`dog
`kinetics
`are
`similar
`for
`in man,
`but
`is
`quickly
`
`is
`
`a
`
`and
`5 mg/kg,
`naltrexone,
`Arterial
`i. v. bolus.
`The
`blood
`was
`
`blood
`allowed
`
`were
`5 mg/kg,
`was
`collected
`clot,
`to
`
`and
`
`to five
`given
`each
`at 2, 5, 10, 15, 30,
`the
`serum
`was
`
`jpet.aspetjournals.org
`
` at ASPET Journals on February 7, 2020
`
`Naloxone,
`dogs
`as a rapid
`60 and
`120 mis.
`frozen
`until
`analyzed.
`naltrexone,
`and
`naloxone
`for
`The
`radioimmunoassay
`et al.
`follows:
`as
`performed
`was
`Berkowitz
`(1975)
`0.2 to 2.0 ng of
`either
`containing
`prepared
`were
`1. Tubes
`for
`standards
`to 4.0
`ng of naltrexone
`in 0.1 ml
`of normal
`human
`naloxone
`or 0.4
`tubes
`were
`prepared
`with
`0.1 ml
`serum
`Assay
`(MIS).
`serum
`in NHS.
`diluted
`sample
`to naloxone
`antiserum
`2. Rabbit
`NaC1,
`1% bovine
`serum
`0.85%
`saline-bovine
`serum
`albumin
`antiserum
`added
`to
`each
`was
`BSA instead
`of antiserum).
`diluted
`was
`nmol/ml)
`[3H]Naloxone
`(10
`(cid:1)sCi/0.5
`to each
`added
`isotope
`and
`0.3 ml of
`the
`diluted
`for
`60 mm.
`temperature
`were
`incubated
`room
`precipitated
`then
`4. The
`antibody-bound
`antigen
`was
`pH 7.3.
`of 0.5 ml of saturated
`(NH(cid:1)(cid:18)SO4,
`a mixture
`once with
`and washed
`5. The
`precipitates
`were
`centrifuged
`(N}L)(cid:1)SO4,
`pH 7.3,
`and
`PBS-BSA.
`of equal
`volumes
`of saturated
`dissolved
`in
`then
`1.0 ml
`of
`distilled
`6. The
`washed
`precipitates
`were
`determined
`in a liquid
`scintillation
`was
`water,
`and
`radioactivity
`consisting
`of3
`parts
`spectrometer
`using
`a cocktail
`toluene
`containing
`Nuclear
`Corp.,
`Boston,
`Mass.)
`5.33
`g of Omnifluor
`(New
`England
`per
`liter
`oftoluene
`plus
`Triton
`(New England
`Nuclear);
`1 part
`X-100
`1.0 ml
`of aqueous
`sample
`was
`added
`to 14 ml
`of
`for
`scintil-
`cocktail
`lation
`counting.
`obtained
`were
`curves
`Standard
`in figure
`example
`is shown
`1.
`The
`serum
`decay
`curves
`polyexponential
`equations
`
`modified
`
`from
`
`of
`
`1:140
`diluted
`was
`pH 7.0
`albumin,
`and
`(PBS-BSA)]
`tube
`(a control
`
`in 0.05 M Na2HPO4,
`[phosphate
`buffered
`the
`0.1 ml of
`diluted
`tube
`contained
`PBS-
`
`at
`
`was
`
`in PBS-BSA
`1:60
`tube.
`The
`tubes
`
`by
`
`the
`
`addition
`
`for
`
`naloxone
`
`and
`
`naltrexone.
`
`An
`
`naloxone
`for
`of
`form
`
`and
`
`naltrexone
`
`were
`
`fitted
`
`to
`
`3.
`
`7.
`
`the
`
`C =
`
`,(cid:1),
`
`by
`
`serum
`
`projection
`a back
`concentrations
`
`(Wagner,
`technique
`1975).
`compared
`by a one-way
`were
`
`Serum
`analysis
`
`and
`half-lives
`of variance.
`
`whose
`1976).
`with
`been
`of
`
`the
`in
`conse-
`1974;
`
`sex,
`
`±
`
`A
`
`is
`
`a
`
`Naloxone
`pharmacokinetics
`Naltrexone
`
`potency
`greater
`as
`evaluated
`opiate-dependence
`The
`dog
`study
`of
`quences
`Patschke
`of naloxone
`
`of
`et
`
`short-acting
`are
`known
`a N-cyclopropyl
`and
`longer
`chemotherapeutic
`(Verebey
`commonly
`a
`is
`hemodynamic
`narcotic
`at.,
`and
`
`and
`antagonists
`Thus,
`
`1977).
`naltrexone
`
`narcotic
`pure
`and man
`for
`rat
`derivative
`duration
`
`we
`in the
`
`antagonist
`(Ngai
`et at.,
`of
`naloxone
`has
`in man
`and
`for
`treatment
`agent
`1975).
`and Mule,
`used
`experimental
`central
`nervous
`(Martin
`and
`studied
`the
`dog.
`
`the
`
`animal
`system
`Sandquist,
`pharmacokinetics
`
`Methods
`
`of either
`dogs
`mongrel
`unmedicated,
`fasted,
`five
`of
`Two
`the
`tracheas
`with
`halothane;
`anesthetized
`kg, were
`10
`weighing
`with
`the
`dogs were mechanically
`ventilated
`and
`were
`100%
`(mean
`0.04
`a mild
`raspiratory
`alkaloais;
`pH 7.46
`02
`±
`Iflamtain
`tO
`was
`placed
`27 ± 6 torr
`cannula
`pCO2
`S.D.),
`(mean
`± S.D.).
`An
`arterial
`was
`inserted
`for
`blood
`sampling,
`and
`a peripheral
`intravenous
`catheter
`for
`administering
`drugs
`and
`fluids.
`End-tidal
`gas was
`sampled
`from the
`endotracheal
`and
`continuously
`monitored
`for
`carbon
`dioxide
`and
`by
`infrared
`gas
`analyzers.
`After
`initial
`instrumentation
`halothane
`and
`stabilization,
`end-tidal
`halothane
`kept
`between
`1.1
`to
`1.25%.
`rectal
`thermometer
`was
`inserted
`temperature
`was maintained
`between
`37.0-38.5#{176}C with
`heating
`and
`blanket.
`
`groups
`about
`intubated
`
`tube
`two
`
`was
`and
`lamp
`
`for publication
`Received
`I ThiS work
`was
`supported
`Army Medical
`by Brooke
`and Williams
`Research
`Meeting
`of American
`2 The
`opinions
`and
`are
`authors
`Army
`or Department
`
`or
`
`not
`
`5, 1978.
`July
`by the University
`part
`in
`Center
`Research
`Protocol
`Fund. The data were
`presented
`of Anesthesiologists,
`Society
`herein
`assertions
`contained
`to be
`construed
`as
`reflecting
`of Defense.
`
`of Utah
`C-33-77,
`in part
`Chicago,
`the
`are
`the views
`
`Fund,
`Research
`Forbes
`by the
`and
`at
`the
`1978 Annual
`Illinois.
`views
`private
`of the Department
`
`of
`
`the
`of
`
`254
`
`Nalox1230
`Nalox-1 Pharmaceuticals, LLC
`Page 1 of 3
`
`
`
`1979
`
`Naloxone
`
`and Naitrexone
`
`Kinetics
`
`255
`
`1
`TABLE
`Serum Concentrations
`
`of naloxone
`
`and naltrexone
`
`Time
`
`mm
`
`2
`5
`10
`15
`30
`60
`120
`
`Naloxone
`(Mean
`± SE.)
`
`pg/mI
`1 .732
`± 0.096
`± 0.086
`1 .320
`± 0.092
`1 .102
`± 0.071
`0.(cid:1)15
`0.462±0.012
`0.342±0.026
`0.197±0.020
`
`Naltrexone
`(Mean
`± SE.)
`
`pg/mI
`1 .390
`± 0.078
`0.724 ± 0.079
`0.446 ± 0.047
`0.368
`± 0.041
`0.283±0.019
`0.215±0.026
`0.149±0.024
`
`F
`
`‘‘
`
`7.68
`26.14
`40.39
`44.21
`65.03
`11.95
`2.44
`
`P
`
`<.05
`<.002
`<.002
`<.002
`<.002
`<.02
`>.2
`
`(cid:1)O
`
`(cid:1)o
`
`(cid:1)o
`
`by
`antiserum
`rabL1
`The lines
`are a least
`
`In
`
`the
`small
`
`very
`
`Downloaded from
`
`jpet.aspetjournals.org
`
`are
`
`et
`
`con-
`
`and
`(Berkowitz
`are
`likewise
`communi-
`conjugation
`(Cone
`et
`the
`exclude
`not
`has
`an
`to
`be
`there
`
`the
`
`during
`dog.
`64
`
`±
`
`71.2
`
`0 Nalfrexone
`(r :0.9988)
`
`Naloxone
`(r:0.9997)
`
`.
`
`4.0
`
`3.0
`
`.520
`
`wz 0 wb
`
`Ui.’
`
`0
`
`0.3’
`
`Al
`
`20
`
`(cid:1)O
`
`(cid:1)..
`
`0
`
`(cid:1)O
`(cid:1)O
`% INHIBITION
`1 .
`Fig.
`to
`naloxone[3H]
`of
`binding
`of
`inhibition
`naloxone
`and naltrexone
`in serum.
`nonradioactive
`squares
`exponential
`curve
`fit.
`
`0 Noltrexone
`
`. Naloxone
`
`say,
`
`but
`
`40
`
`20
`
`20
`
`.0
`
`0.3
`
`0.2
`
`0.1
`
`wz0(cid:1)
`
`(cid:1)0.4
`
`z
`
`N-dealkylated
`the
`contrast,
`In
`communication).
`sonal
`recognized
`not
`naloxone
`of
`metabolites
`jugated
`et at.,
`naltrexone
`of
`metabolites
`similar
`1975);
`the
`personal
`(B. A. Berkowitz,
`not
`recognized
`probably
`by
`naltrexone
`is metabolized
`dog
`cation).
`produced
`amounts
`of
`naltrexol
`also
`with
`cannot
`and
`Gorodetzky,
`1976). We
`at.,
`Cone
`1974a;
`metabolism
`in
`the
`dog
`naloxone
`as
`of naloxol
`presence
`is not
`likely
`it
`species;
`however,
`this
`studied
`in
`been
`Thus,
`(Berkowitz
`important
`metabolite
`at.,
`1975).
`the
`radioimmunoas-
`with
`interferring
`should
`no metabolites
`be
`methods
`is needed.
`by more
`specific
`confirmation
`similarities
`with
`previous
`in dogs
`has
`kinetics
`ofnaloxone
`The
`of
`i.v.
`naloxone
`produced
`a
`serum
`In
`the
`rat,
`5 mg/kg
`work.
`xg/ml
`at
`5 mm
`(Ngai
`1976);
`concentration
`of
`1.45
`± 0.1
`at.,
`et
`± 0.086
`in the
`present
`study,
`the
`concentration
`was
`1.320
`(cid:1)tg/ml
`at
`30
`5 mm.
`However,
`the
`half-lives
`elimination
`were
`nun
`in
`the
`rat
`and
`71.2 mm
`for
`The
`half-lives
`in man
`12 mm vs.
`and
`in
`the
`dog
`were
`quite
`similar,
`±
`8.9
`mm,
`respectively
`(Ngai
`al.,
`1976).
`et
`In
`the
`rat,
`naloxone
`and
`naltrexone
`serum
`decay
`curves
`after
`i.v.
`injection
`Thus,
`naltrexone
`serum
`kinetics
`are
`dogs.
`Our
`naltrexone
`kinetics
`not
`have
`man
`as
`the
`latter
`been
`after
`naltrexone
`administration
`1974b;
`Verebey
`et
`at.,
`administration,
`there
`olism
`(75% dose)
`(Kogan
`1977).
`potent
`is more
`In many
`species
`naltrexone
`has
`twice
`naltrexone
`than
`naloxone.
`In
`the
`rat
`and Mule,
`1975).
`duration
`3 times
`the
`(Verebey
`duration
`have
`been
`greater
`potency
`longer
`and
`ebey
`and Mule,
`However,
`the
`dog
`while
`in
`1975).
`of
`naltrexone
`that
`of
`naloxone,
`the
`durations
`twice
`same
`(Martin
`Martin
`and
`Sandquist,
`a!.,
`1973;
`longer
`duration
`over
`naloxone
`might
`naltrexone
`prolonged
`half-life,
`a longer
`retention
`of naltrexone
`of
`or
`the
`presence
`an
`active
`metabolite.
`Berkowitz
`compared
`et at.
`(1976)
`in
`tions
`of naloxone
`and
`naltrexone
`dose;
`there
`were
`no major
`differences
`the
`brain
`profile
`of
`these
`drugs.
`Since
`rat
`of
`naltrexone
`is
`the
`same
`for man,
`bound)
`and
`is also
`constant
`over
`a wide
`(Ludden
`is unlikely
`that
`et
`at.,
`1976),
`it
`of
`naltrexone
`action
`between
`dog
`and
`longer
`cerebral
`retention.
`As
`noted
`our
`in
`the
`shown
`
` at ASPET Journals on February 7, 2020
`
`essentially
`have
`(Berkowitz
`quite
`similar
`comparable
`acute
`to
`24
`al.,
`et
`first-pass
`
`and
`hr
`
`72
`
`et
`in
`
`et
`
`identical
`1976).
`at.,
`rats
`and
`studies
`in
`to
`chronic
`oral
`(Cone
`at.,
`After
`oral
`metab-
`
`1977).
`hepatic
`
`are
`done
`and
`
`over
`Kogan
`1976;
`considerable
`et
`at.,
`
`is
`
`acting
`longer
`and
`and
`potency
`the
`In man
`a similar
`observed
`(Ver-
`the
`potency
`are
`1974).
`be
`due
`in the
`
`the
`The
`to
`brain
`
`a
`
`is
`et
`
`of
`
`serum
`the
`
`and
`after
`rat
`between
`plasma
`and
`range
`the
`man
`
`concentra-
`brain
`a 5 mg/kg
`the
`serum
`protein
`binding
`(about
`20-25%
`dog
`concentrations
`of
`different
`durations
`and
`is
`due
`
`i.v.
`or
`
`rat
`
`to
`
`ics
`
`above,
`dog
`as
`
`showed
`results
`previously
`
`similar
`in
`the
`
`naltrexone
`rat.
`Although
`
`kinet-
`not
`
`$0
`
`20
`
`30
`
`50
`
`60
`TIME (mm)
`
`70
`
`80
`
`90
`
`00
`
`110
`
`2. Comparative
`Fig.
`after
`a dose
`dogs
`five dogs.
`
`serum disposition
`5 mg/kg
`iv.
`Results
`
`of naloxone
`are
`the
`
`and naltrexone
`average
`± SE.
`
`of
`
`in
`of
`
`Results
`
`per mffliliter)
`concentration
`serum
`The
`best
`described
`was
`a 5 mg/kg
`following
`oxone
`e#{176}#{176}(cid:1)5’+ 0.5478
`equation
`biexponential
`C =
`was
`characterized
`disappearance
`mm).
`Naltrexone
`
`0.3808
`
`e#{176}#{176}#{176}(cid:1)5’(fig. 2).
`The
`serum
`1.7989
`e(cid:1)0(cid:1)#{176}(cid:1)t
`phase
`was
`71.2
`±
`8.9 mm
`(mean
`the
`elimination
`85.1
`±
`9.0 min
`naltrexone.
`These
`naloxone
`and
`were
`significantly
`different
`not
`(F(i,
`P >
`8)
`the
`distribution
`phase
`serum
`initial
`and
`were
`8.9
`naltrexone
`0.9
`±
`2.4
`these
`significantly
`different
`were
`(F(l,
`serum
`concentration
`naloxone
`was
`of
`naltrexone
`serum
`concentrations
`from
`
`=
`
`±
`
`1.20,
`half-lives
`0.3
`min,
`43.1,
`=
`8)
`significantly
`2 to
`60 mm
`
`.002).
`higher
`(table
`
`(micrograms
`i.v.
`bolus
`1.2162
`
`for
`
`the
`and
`
`nal-
`of
`the
`by
`
`e#{176}#{176}#{176}(cid:1)’(t
`=
`by
`C
`half-life
`±
`S.E.)
`half-lives
`During
`.2).
`naloxone
`for
`respectively;
`P <
`
`=
`for
`for
`
`The
`than
`1).
`
`Discussion
`
`This
`naltrexone,
`naloxone
`droxynaloxone,
`not
`studied,
`naltrexone
`
`radioimmunoassay
`but
`the
`(reduction
`
`antibody
`of
`the
`“naloxol”)
`is
`probable
`it
`(naltrexol)
`is
`
`also
`
`is
`
`naloxone
`for
`sensitive
`quite
`a metabolite
`recognizes
`also
`to
`produce
`ketone
`group
`C-6
`1975).
`Although
`(Berkowitz
`a!.,
`et
`metabolite
`that
`the
`equivalent
`recognized
`(B. A. Berkowitz,
`
`or
`of
`hy-
`
`of
`per-
`
`Nalox1230
`Nalox-1 Pharmaceuticals, LLC
`Page 2 of 3
`
`(cid:1)
`(cid:1)
`(cid:1)
`(cid:1)
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`
`jpet.aspetjournals.org
`
` at ASPET Journals on February 7, 2020
`
`256
`
`Pace
`
`et al.
`
`Vol. 208
`
`strictly
`oral
`and
`tively.
`dog.
`and
`life.
`An
`
`and
`
`the
`
`comparable,
`revealed
`naltrexone
`half-life
`a primary
`is not
`too
`This
`the
`prolonged
`Thus,
`not
`in dog
`is probably
`
`urine
`a half-life
`of
`3 hr
`dissimilar
`effect
`not
`
`serum
`of
`1.1
`(Verebey
`the
`from
`of
`naltrexone
`explained
`by
`
`hr
`
`in man
`et
`at.,
`
`profile
`(Cone
`1976),
`et
`at.,
`of
`half-life
`in man
`a difference
`
`after
`1974b)
`respec-
`in
`1.4
`hr
`rat
`and
`in half-
`
`(naltrexol)
`metabolite
`Naltrexol
`has
`species.
`in
`not
`and
`Mule,
`(Verebey
`naltrexone
`man
`the major
`biotransformation
`trexol
`with
`eventual
`urinary
`Dayton
`and
`Inturrisi,
`1976;
`trexol
`has
`been
`reported
`administration
`(Cone
`et
`excretion
`of naltrexone
`administered
`dose
`and
`Inturrisi,
`1976).
`naltrexone
`is conjugated
`1974a;
`and
`Gorodetzky,
`to
`relate
`longer
`duration
`persistence
`an
`active
`metabolite
`metabolic
`of naltrexone
`in rat
`of naltrexone
`remains
`unexplained
`
`active
`all
`
`is
`
`Cone
`
`the
`of
`fate
`
`has
`1/50
`1975;
`product
`excretion
`Verebey
`persist
`1974b).
`not well
`in
`urine
`no
`excreted
`1976).
`of
`
`to
`
`at.,
`are
`found
`Essentially
`and
`
`been
`to
`Cone
`
`found
`1/12
`the
`at.,
`et
`naltrexone
`et
`
`but
`in some,
`of
`potency
`In
`1974b).
`is nal-
`1974b;
`nal-
`oral
`and
`the
`
`the
`the
`
`in
`the
`species.
`
`of
`(Cone
`at.,
`in man
`1976);
`at.,
`et
`after
`to
`6
`days
`up
`the metabolism
`rat
`In
`1% of
`less
`than
`defined;
`(Dayton
`hr
`first
`24
`in
`the
`in
`dog;
`found
`is
`naltrexol
`(Cone
`urine
`in the
`et at.,
`reasonable
`Thus,
`it appears
`naltrexone
`in man
`to
`not
`found
`dog.
`Until
`is defined,
`long
`duration
`in that
`
`Acknowledgments
`
`Dr. Ralph
`supply
`
`thank
`We
`generous
`the
`radioimtnunoa.ssay
`Institute
`of Molecular
`
`Jacobsen
`of naloxone
`was
`kindly
`Biology
`
`of Endo
`HC1
`and
`provided
`by
`(Nutley.
`N.J.).
`
`Laboratories
`naltrexone
`Dr.
`Barry
`
`City,
`(Garden
`HC1. Antiserum
`A.
`Berkowitz
`
`for
`N.Y.)
`the
`for
`of Roche
`
`BERKOWITZ,
`and
`onist
`Drugs,
`ed.
`York,
`1976.
`E.
`J. AND
`CONE,
`naloxone
`(NOX)
`469,
`1976.
`E.
`J., GORODETZKY,
`C. W.
`CONE,
`identification
`of
`fJ-hydroxynaltrexone.
`E.
`J., GORODETZKY,
`C. W. AND
`CONE,
`of naltrexone
`and metabolites
`in man.
`H. E. AND
`C. E.: The
`DAYTON,
`INTURRISI,
`in man,
`monkey,
`rabbit,
`and
`rat.
`Drug
`M.
`J.,
`K.
`KOGAN,
`VEREBEY,
`AND
`MULE,
`availability
`and
`other
`pharmacokinetic
`acute
`and
`chronic
`oral
`administration.
`col.
`18:
`29-34,
`1977.
`T. M., MALSPEIS,
`J. D.,
`L,
`BAGGOT,
`LUDDEN,
`R. H.:
`Tritiat.ed
`naltrexone
`AND
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`in mice.
`J.
`tissue
`species
`and
`distribution
`W. R.,
`C. G. AND
`THOMPSON,
`EADES,
`MARTIN,
`dependent
`dog
`for
`suppression
`studies
`and
`antagonists.
`Fed.
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`32:
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`W. R.
`V. L.: A sustained
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`AND
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`Arch. Gen.
`antagonists.
`Psychiatry
`30:
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`1974.
`J.C.,
`S. H.,
`BERKOWITZ,
`B. A., YANG,
`NGAI,
`HEMPSTEAD,
`Basis
`Pharmacokinetics
`of naloxone
`in rats
`and
`in man:
`1976.
`short
`duration
`of action.
`Anesthesiology
`44:
`398-401,
`J.,
`J.
`W.,
`D.,
`HESS,
`AND
`PATSCHKE,
`EBERLEIN,
`TARNOW,
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`Antagonism
`of morphine
`and
`naloxone
`in
`dogs:
`the
`coronary
`circulation.
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`special
`reference
`to
`1977.
`VEREHEY
`metabolism:
`VEREBEY,
`Disposition,
`Pharmacol.
`WAGNER,
`Intelligence
`
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`SPECTOR,
`antagonist
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`
`antag-
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`C. H.: Mechanisms
`S. AND
`action.
`In Tissue
`Responses
`to Addictive
`analgesic
`and D. H. Clouet,
`Spectrum
`Publications,
`Inc., New
`
`GORODETZKY,
`in man
`
`and
`
`metabolites
`C. W.: New
`several
`laboratory
`animal
`
`of naltrexone
`species.
`Fed.
`
`(N)
`Proc.
`
`and
`35:
`
`AND
`
`225,
`
`isolation
`S. Y.: Biosynthesis,
`YEH,
`1974a.
`Pharmacologist
`16:
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`excretion
`S. Y.: The
`urinary
`YEH,
`1974b.
`2: 506-512,
`Drug Metab.
`Dispos.
`profiles
`of naltrexone
`excretion
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`4: 474-478,
`1976.
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`Estimation
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`the
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`
`Pharm.
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`S0K0L05KI,
`in
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`J. A.: The
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`
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`T. D.,
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`712-716,
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`
`for
`
`687,
`
`release
`
`depot
`
`J. AND
`for
`its
`
`and
`
`S. G.
`several
`
`FRANK,
`from
`1976.
`the morphine
`of narcotic
`
`for
`
`narcotic
`
`SPECTOR,
`potency
`
`S.:
`and
`
`ZIMMERMAN,
`
`G.:
`with
`525-533,
`
`effects
`49:
`
`and
`
`pharmacokinetics
`357-363,
`1975.
`R. B.: Naltrexone:
`chronic
`dosing.
`Clin.
`
`K.,
`
`K. AND MULE,
`J.: Naltrexone
`S.
`Am.
`J. Drug
`status.
`Current
`J., MULE,
`S.
`VOLAVKA,
`and
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`effects
`20:
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`1976.
`Ther.
`J. G.:
`Fundamentals
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`
`pharmacology,
`2:
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`AND
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`
`J.
`after
`
`Pharmacokinetics,
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`1975.
`
`Chap.
`
`2, Drug
`
`References
`
`BERKowITz,
`naloxone:
`504,
`1975.
`
`S. H., HEMPSTEAD,
`B. A., NGAI,
`Use
`of a new radioimmunoassay.
`
`J. AND
`SPECTOR,
`J. Pharmacol.
`
`S.: Disposition
`Ther.
`195:
`
`Exp.
`
`of
`499-
`
`Send
`City,
`
`reprint
`Utah
`
`requests
`84132.
`
`to: Dr. Nathan
`
`L. Pace,
`
`50 N. Medical
`
`Drive,
`
`Salt
`
`Lake
`
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`Page 3 of 3
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