Tira JOURNAL
`OF I’IIARMACOLOGY
`© 1973
`by The Williams
`Copyright
`
`EXPERIMENTAL
`AND
`& Wilkins
`C.
`
`TJIF.RAPEITICS
`
`VI.
`Printed
`
`1S7. No.
`in
`U.S.A.
`
`3
`
`DISPOSITION
`
`OF
`
`NALOXONE-7,8-3H
`
`A(cid:1)D
`
`NARCOTIC-DEPENDENT
`
`IN
`
`NORMAL
`
`MEN’
`
`JACK
`
`FlSIL’vlA(cid:1)
`
`,
`
`lIOWARI)
`
`ROFF\VARG
`
`ANI
`
`(cid:1))
`
`LEON
`
`IIELLMAN
`
`Jn.’(cid:1)tiiu1e
`
`Steroid
`for
`.llontefiore
`
`Research,
`lbs
`pita!
`
`Division
`a ad Medical
`
`of
`
`P.s!;chzair!,
`
`(‘en
`
`icr,
`
`and
`Bronx,
`
`Division
`New
`
`York
`
`of Oncology,
`
`Accepted
`
`for
`
`publication
`
`August
`
`3, 1973
`
`A B ST H A C 1’
`
`FISFIMAN,
`in
`7 ,8-’H
`580, 1973.
`
`JACK,
`nornial
`
`HowAna
`aiul
`
`ROFFWARG
`narcotic-(lel)en(lent
`
`ANI)
`
`LEoN
`men.
`
`1IELLMAX:
`.J. Pharmaeol.
`
`Disposition
`Exp.
`
`of
`Them.
`
`naloxone-
`187:
`575(cid:1)
`
`Naloxone-7
`the
`same
`naloxone-7
`
`fl1..ailItPlIalI(P
`
`, S-nil
`liorlual
`,8-(cid:1)H
`an(l
`
`liCVPl(cid:1)
`
`\V(’I(’
`
`but
`
`almillitercd
`subject
`also
`studied
`Witl(cid:1)(lra\Val.
`
`:111(1
`
`its
`in
`
`Iii
`the
`iate
`
`orally
`
`oii
`
`separate
`(cid:1)Fhe
`fate
`1)0th
`
`occasions
`
`to
`
`of
`while
`mapi(l
`
`ilitmavellous
`au
`heroin
`but
`in-
`
`uriiiarv
`hours.
`
`concentrations
`
`l)lasrna
`naloxone
`Plasma
`
`was
`tuttle
`was
`after
`(‘xee(’(ling
`lOW with
`a metabolized
`iii
`clearance
`rate
`liters,
`90 minutes
`
`of
`a mapi(l
`form.
`naloxolte
`and
`2500
`
`of
`
`co11(cid:1)l)lete,
`of
`naloxolle
`quickly
`metabtlic
`about
`
`200
`
`alal
`illtmavellouslv
`was
`(Iirposiitioli
`an
`opiat.e-depelnlent
`(uses
`the
`all
`over
`72
`dose
`disappearance.
`of
`volume
`of
`The
`calculated
`as
`liters/day,
`
`(‘xaliulled.
`subject
`exereta)lI
`Initial
`Oral
`(listril)ution,
`from
`the
`respectively.
`
`ilitravellolls
`
`entere(l
`half-life
`studies
`
`l)lasnla
`and
`were
`
`Nalox(cid:1)ne
`(Blumberg
`is virtually
`1967).
`to
`dote
`oratories,
`active
`postathlict
`the
`latter
`tages
`of
`
`a
`
`parenterally
`taken
`of
`sonic
`n(cid:1)oto,
`
`orally.
`of
`1970;
`
`poteiit
`is
`1961
`; Foldes
`et a!.,
`of agonist
`activity
`free
`is PresentlY
`It
`ii(cid:1)
`narcotic
`overdosage
`Gardeit
`City,
`ilivestigation
`chemotherapy
`suffers
`it
`purpose,
`duration
`short
`from
`and
`the
`\Vith
`its metabolites
`
`a
`
`as
`
`narcotic
`alltagollist
`1963)
`which
`et at.,
`(Jasinski
`et a!.,
`au
`as
`aitti-
`Endo
`Lab-
`also
`under
`agent
`1971).
`disadvan-
`
`clinical
`use
`(Narcan,
`and
`N.Y.)
`a
`therapeutic
`(Zaks
`et a!.,
`from
`the
`
`is
`
`of
`low
`:t
`exception
`in
`human
`1971),
`
`action
`when
`effectiveness
`of
`the
`urine
`little
`
`\Veillsteill
`
`et a!.,
`
`iii
`For
`
`given
`wheit
`idelitity
`(Fuji-
`is knowll
`
`Received
`work
`‘ This
`Institute
`tional
`MH 21365-01,
`of Health,
`R1153.
`Grant
`
`for
`
`and
`
`January
`publication
`supported
`has
`been
`of Mental
`Health
`the New
`York
`by
`the
`Clinical
`
`by
`
`in
`
`1973.
`11,
`part
`by Na-
`(.rant
`1 HO!
`l)epartrnent
`City
`Research
`Center
`
`reprint
`Send
`Hospital
`Mont.ifiore
`210th
`St., Bronx.
`N.Y.
`
`requests
`to:
`an(l Medical
`10467.
`
`Dr.
`
`J.
`Center,
`
`Fishman,
`111 H.
`
`of
`fate
`the
`about
`dispositioii
`the
`al)Otlt
`particular
`be
`of
`for
`its
`reasons
`ineffectiveness
`to
`circumvent
`
`value
`short.
`and
`these
`
`lialoXolte
`of
`
`Information
`in mait.
`iii man
`would
`iialoxoiie
`siiice
`it may
`reveal
`the
`duratioll
`of
`action
`an(l
`oral
`the
`permit
`(lesigli
`of methods
`un(lesirable
`features
`of
`
`its
`
`(cid:1)harInacolog3’.
`,rh
`synthesis
`specific
`activity
`(Fishmall
`al.,
`et
`the
`substrate
`for
`material
`in man.
`7 ,8-’H
`a
`veiiouslv
`alid
`tribut.ioIl
`effect
`
`to
`
`alld
`narcotic
`
`of
`
`volunteer
`orally
`
`urinary
`
`of
`
`excretion.
`agonists
`
`,8-’H
`naloxolle-7
`isotope
`biological
`aIl(l
`the
`I)rovided
`1973)
`the
`of
`investigation
`a(lmuhistere(l
`\Ve
`have
`itormal
`sul)ject
`and
`followed
`its
`(cid:1)Fo
`
`high
`of
`stability
`necessary
`fate
`of
`this
`naloxoite-
`both
`iiitra-
`I)lasrna
`dis-
`examine
`the
`dispositioll
`of
`the
`a(lnhilI
`l(cid:1)ave
`we
`oi )iate-del
`a volunteer
`heroin
`luailltellallee
`(cid:1)s.:is
`opiate-free.
`with
`I )art
`i(ular
`
`on
`
`istered
`)endent
`theit
`of
`the
`
`and
`results
`on
`
`Ihe
`emphasis
`
`i ialoxone,
`, 8-’lI
`to
`while
`
`011
`
`intravenous
`naloxone-7
`subject
`again
`these
`
`lie
`
`(cid:1)VlWll
`tidies
`
`st
`
`(cid:1))harn(cid:1)acokil1eti(s
`this
`conimullicatioll.
`
`575
`
`of
`
`llitlOXOlle
`
`ale
`
`reporte(l
`
`in
`
`Page 1
`
`RB Ex. 2032
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`(cid:1)
`(cid:1)
`

`

`576
`
`FISHMAN
`
`ET
`
`AL.
`
`Vol.
`
`187
`
`overnight
`after
`naloxone-7,8-3H,
`which
`represented
`j(cid:1)g
`p.o.
`To
`prevent
`100
`subject
`Fit
`received
`specific
`activity
`of
`0.5
`contained
`4
`and
`4.5
`big.
`each
`were
`collected
`into
`specific
`intervals
`and
`red
`cells
`their
`radio-
`and
`red
`blood
`The
`(supplied
`by
`bleached
`with
`in
`toluene-
`background.
`a
`Packard
`in
`with
`suitable
`an
`internal
`of
`samples
`in
`each
`of
`naloxone
`and
`and
`the
`extracts
`solvent.
`The
`ethyl
`of
`purified
`on
`preparative
`in
`the
`system
`chioro-
`(100:60:2).
`zone
`acid
`naloxone
`by
`was
`eluted
`the
`
`a
`
`The
`visualized
`with
`naloxone
`
`ethanol
`was
`
`at
`plasma
`
`of
`
`morning
`the
`administered
`received
`JA
`fasting.
`25 mc/mnml,
`specific
`iv.
`and
`(cid:1)g
`dose
`of
`symptoms,
`withdrawal
`with
`na1oxone-7,8-(cid:1)lI
`doses
`c/mrnol
`arid
`10 ml
`Blood
`samples
`containers
`heparin
`-treated
`The
`after
`administration.
`1)y centrifugation
`were
`separated
`was
`determined.
`active
`content
`NCS
`digested
`cells
`were
`first
`in
`Ill.),
`Chicago,
`Amershain/Searle,
`counted
`and
`then
`benzoyl
`peroxide,
`no
`phosphor
`show
`above
`counts
`to
`directly
`counted
`The
`plasma
`was
`in diotol
`counter
`liquid
`scintillation
`by means
`quenching
`corrections
`the
`plasma
`of
`standard.
`Aliquots
`.-(cid:1)..10 mg
`with
`study
`diluted
`acetate
`ethyl
`extracted
`with
`after
`removal
`were
`counted
`were
`then
`acetate
`extracts
`thin-layer
`chromatography
`form-methanol-acetic
`to
`corresponding
`absorption
`ultraviolet
`specific
`and
`the
`determined.
`intervals
`at.
`collected
`Urines
`were
`collection
`each
`Aliquot.s
`of
`Urine
`In
`every
`and
`counted.
`with
`water
`complete
`obtain
`were
`made
`to
`were
`determinations
`ereatinine
`Aliquots
`was
`achieved.
`that
`this
`frozen
`urine
`collections
`were
`counted
`was
`The water
`obtained
`so
`was
`specific
`activity
`obtained
`essen
`indicating
`background
`tritium
`the
`biological
`stability
`of
`were
`urine
`Other
`aliquots
`the
`to (ontinuoliS
`7.8
`arid were
`were
`also
`and
`tiori
`for
`24
`(7 : 3) . The
`chloroform-ethanol
`dryness
`and
`to
`were
`taken
`counting
`carried
`counted.
`All
`Tri-Carb
`liquid
`48.7%.
`efficiency
`of
`
`a
`
`in
`
`Subject
`activity
`125
`
`the
`
`of
`
`was
`
`free
`
`activity
`
`Methods
`
`(N -allylnoroxymorphone)
`hydrochloride
`from
`obtained
`base
`was
`hydrochloride
`
`the
`free
`the
`
`ob-
`was
`Labora-
`an aqueous
`precipitation
`
`Endo
`from
`by
`
`prepared
`wa.s
`1973)
`and
`ci a!.,
`a specific
`activity
`
`in
`was
`
`these
`diluted
`of 0.5
`
`labora-
`with
`c/rnmol
`
`to
`
`a
`was
`
`normal
`free
`prior
`
`man
`
`a
`
`was
`
`the
`
`the
`
`of
`
`Naloxone
`tamed
`as
`tories.
`The
`of
`solution
`ammonia.
`with
`Naloxone-7,8-3H
`tories
`(Fishman
`inert
`material
`and
`25 mc/mmol.
`42-year-old
`was
`Subject
`JA
`81
`from
`all medication
`weighing
`kg who
`and
`to
`the
`study.
`Sub-
`during
`immediately
`was
`FR
`man
`weighing
`64
`kg
`jeet
`a
`23-year-old
`of
`a history
`dependence.
`At
`time
`with
`opiate
`study,
`first
`being
`maintained
`on
`of
`he was
`35 mg
`of
`a day
`the Montefiore
`at
`total
`heroin
`Clinical
`Heroin
`maintenance
`Hospital
`Center.
`terminated
`methadone
`in
`conjunction
`then
`and
`small
`doses
`with
`of
`tranquilizers
`was
`substituted.
`regimen
`with
`This
`decreasing
`amounts
`of metha-
`was
`continued
`done
`for
`about
`five weeks
`at which
`the methadone
`time
`was
`stopped
`completely.
`The
`study
`with
`second
`naloxone-7,8-3H
`was
`carried
`out
`one week
`later
`while
`the
`subject
`was
`receiving
`only
`chlorpromazine
`and
`diazepam.
`The
`naloxone-7,8-3H
`was
`dissolved
`distilled
`propylene
`A weighed
`the
`dose
`was
`retained
`counting
`mainder
`(1-2 ml) was
`as
`antecubital
`vein.
`The
`injected
`determined
`and
`of
`the
`empty
`dose
`calculation
`the
`administration
`a weighed
`glycol
`solution
`was
`diluted
`
`glycol.
`for
`injected
`weight
`by
`the
`full
`and
`administered.
`the
`amount
`of
`with
`orange
`
`freshly
`in
`aliquot
`and
`the
`a bolus
`into
`of
`the
`material
`weight
`difference
`thus
`permitted
`oral
`For
`propylene
`juice
`
`of
`me-
`the
`
`and
`
`was
`syringe
`
`of
`
`Urinary
`
`1
`
`TABLI’
`ra(lioaciiviiy
`(as
`
`of
`in,istraiion
`
`excretion
`adni
`
`after
`of
`dose)
`
`.(cid:1).
`
`naloxone-3H
`
`JA
`
`FR
`
`i.v.
`
`Oral
`
`.
`
`eroin
`lv.)
`
`Narco-
`tic-free
`(i.u.)
`
`Dose
`
`(cpm
`
`X
`
`106)
`
`10.35
`
`8.14
`
`6.87
`
`7.24
`
`collections
`Urine
`0-Ghr
`(i-l2hr
`12-24hr
`24-48hr
`48-72hr
`
`37.7
`6.2
`9.5
`9.0
`1.4
`
`23.5
`11.1
`12.1
`9.1
`3.3
`
`24.7
`9.4
`18.3
`11.1
`4.3
`
`37.4
`4.1
`10.1
`5.1
`3.6
`
`Total
`
`64.8
`
`59.1
`
`67.8
`
`60.3
`
`hours.
`for
`diluted
`were
`efforts
`all
`case
`and
`collections,
`ensure
`used
`to
`of
`the
`combined
`and
`lyophilized.
`and
`the
`highest
`1 cprn/rnl
`above
`tially
`complete
`at. C-7
`and
`C-8.
`adjusted
`pH
`to
`ether
`extrac-
`extracted
`with
`organ
`ic
`extracts
`residues
`were
`a Packard
`in
`with
`
`72
`
`an
`
`the
`
`out
`counter
`
`,
`
`of
`subjected
`hours
`
`was
`scintillation
`
`Results
`
`adnlillistered
`(cid:1)Flie (loses
`cretioll
`of
`radioactivity
`table
`1.
`‘I’he
`ill
`given
`with
`to
`37 (cid:1)
`24
`rapid
`first.
`hours
`with
`the
`a(cid:1))pearil1g
`the
`filial
`
`6
`
`ill
`
`and
`all
`
`to
`
`cx-
`are
`is very
`
`the
`four
`all
`ill
`(lose
`little
`72
`
`tllillarV
`studies
`caseS
`appearing
`radioactivity
`hours.
`The
`
`iii
`
`cx-
`
`in
`excretu)ll
`of
`the
`very
`48
`
`Page 2
`
`

`

`1973
`
`l)ISPOSITION
`
`OF
`
`NALOXONE
`
`IN MAN
`
`577
`
`the
`ill
`extractable
`subject,
`
`material
`none
`
`of
`
`it
`
`In
`
`hours
`
`all
`
`was
`was
`normal
`slowly
`In
`FR,
`25%
`after
`
`form
`conjugated
`organic
`with
`oral
`dose
`the
`the
`to
`compared
`(cid:1)s’helI
`opiate-
`of
`the
`case
`the
`the
`excretion
`within
`the
`he
`heroni
`when
`011
`withdrawal.
`(cid:1)l’hereafter,
`while
`o(cid:1)i heroin
`was
`faster
`excreted
`heilig
`somewhat
`Opiate-flee..
`The
`total
`four
`stu(lies
`was
`quite
`67 #{182}(cid:1)of
`the
`(lose.
`The
`(lose
`
`the
`more
`dose.
`subject,
`was
`37 (cid:1)
`to
`excretion
`the
`eventual
`total
`67
`to
`61 % when
`excretion
`all
`to
`from
`ranging
`59
`the
`the
`remainder
`of
`of
`time,
`since
`fecal
`excretion
`
`ill
`
`Plasma
`
`to
`
`all(l
`the
`
`in
`
`The
`
`140
`
`120
`
`100
`
`SI
`
`160
`E
`
`40
`
`20
`
`0
`
`‘
`
`. -.
`
`On Heroin
`
`#{176}
`
`0
`
`Off Narcotics
`
`1
`
`2
`
`3
`
`4
`
`HOURS
`
`.
`
`a
`
`7
`
`2.
`
`FIG.
`naloxone-7
`eat
`subject
`
`radioactivity
`Plasma
`, 8-3H administration
`while
`on
`heroin
`
`intravenous
`after
`opiate-depend-
`to
`after
`withdrawal.
`
`and
`
`IS ulikilowli
`was
`not
`
`at
`
`Ifloni-
`
`follow-
`
`of
`is
`
`(lose.
`dose
`ceeds
`study
`
`The
`reaches
`to
`for
`
`by
`
`from
`iadioactivitv
`Plasma
`a maximum
`at. 30 millutes
`(lecay
`faster
`than
`in
`the
`the
`next
`hours.
`After
`
`the
`arid
`intravenous
`that,
`a
`
`3
`
`oral
`pro-
`
`time
`
`creted
`since
`solvents.
`was
`excreted
`intravenous
`dependent
`first
`6
`compared
`however,
`with
`the
`higher,
`urinary
`similar
`fate
`this
`tored.
`change
`The
`iii
`ultravellous
`both
`ilig
`,8-3H
`naloxone-7
`graphically
`recorded
`specific
`the
`comparisoll,
`been
`have
`experiment
`1 x 10(cid:1)
`cpm.
`dose
`of
`ance
`curve
`reveals
`presumably
`reflecting
`slower
`of
`decrease
`that
`the
`plasma
`already
`very
`small
`appeared
`in
`the
`(20
`hours).
`Oral
`surprisingly
`rapid
`the
`plasma
`with
`already
`containing
`the
`eorrespondiiig
`
`rate
`time
`
`and
`
`SJ)ecific
`oral
`Ilornurl
`figure
`activity
`adjusted
`illtlavenOus
`initial
`rapid
`ILl!
`(listlil)UtiOll,
`for
`the
`radioactivity
`it
`had
`Plasnia
`iiext
`naloxone-7,8-H
`appearance
`the
`initial
`75%
`of
`sample
`
`next
`
`the
`from
`
`activity
`administration
`JA,
`subject,
`direct
`1. To
`J)elrnit
`each
`values
`from
`to
`common
`a
`disappear-
`component
`followed
`5 hours.
`contelit
`completely
`saliij)le
`measured
`results
`in
`1a(lioactivity
`of
`15-minute
`radioactivity
`the
`h(cid:1)t
`raves
`
`a
`At
`was
`dis-
`
`a
`
`in
`
`sample
`
`iii
`ious
`
`120
`
`00
`
`(cid:1)60
`
`C
`
`40
`
`20
`
`.
`
`0
`
`.
`
`intravenous
`Ooral
`
`1
`
`2
`
`3
`HOURS
`
`4
`
`5
`
`6
`
`radioactivity
`1. Plasma
`naloxone-7,8-3H
`
`FIG.
`oral
`subject.
`
`and
`mal
`
`after
`administration
`
`intravenous
`to
`
`nor-
`
`is
`plateau
`OmilY minimal
`‘I’he
`plasma
`opiate-depelident
`, 8-3H
`naloxone-7
`niaifltenlallce
`heroin
`are
`recorded
`drawal
`also
`beeii
`adjusted
`have
`1 x 10(cid:1)
`to
`cpni,
`allow
`difference
`between
`( 1 5-minute)
`initial
`is
`about
`30%
`The
`rate
`of
`however,
`so
`curve
`taini
`dose
`
`for
`these
`
`l)lasIIl:L
`
`the
`
`higher
`decay
`it
`that
`heroin
`the
`from
`approximation
`an
`radioactivity
`
`ill
`that
`Ill
`intercepts
`study
`of
`contained
`
`for
`apparelit
`left
`coutits
`radioactivity
`sul)ject,
`adniinistratioii
`alld
`in
`
`the
`in
`
`the
`dat:,.
`FR.,
`
`with
`hours
`3
`iiext
`sample.
`20-hour
`in
`obtained
`after
`intravenous
`both
`whell
`liarcOtic
`after
`These
`2.
`figure
`common
`a
`to
`comparison.
`two
`stu(lieS
`
`the
`
`of
`
`The
`is
`
`on
`with-
`results
`dose
`main
`iii
`the
`(cid:1)vhich
`state.
`faster,
`is
`disappearance
`3 hours.
`ob-
`To
`the
`percentage
`of
`in
`the
`body
`
`concelit
`ratioli
`narcotic-free
`experiiiieiit
`the
`
`at
`
`the
`
`total
`
`38 ml
`used
`we
`volume
`Plaslila
`l)lasma
`give
`to
`b.wt..
`l)C(cid:1)
`kg
`Plasma
`2.35
`liters
`subject
`for
`liters
`of 3.0
`volumes
`percentage
`these
`values,
`FR. With
`for
`subject
`times
`in
`at
`the
`l)lood
`various
`cotitaineci
`can
`be
`calculated.
`Fifteen
`minutes
`experiments
`3.5
`after
`administration
`to
`sul)ject
`JA,
`and
`2.5%
`the
`of
`intravenous
`and
`oral
`(lose
`radioactivity,
`respectively,
`is
`the
`total
`blood
`cOlltaille(l
`ill
`ume.
`(cid:1)Fhe
`percentages
`subject.
`FR
`arc
`
`of
`
`of
`
`a value
`calculated
`JA and
`the
`
`all
`
`vol-
`2.0%
`
`have
`
`ill
`
`for
`
`Page 3
`
`(cid:1)
`(cid:1)
`(cid:1)
`

`

`578
`
`FISIIMAN
`
`ET
`
`AL.
`
`Vol.
`
`187
`
`heroin
`that
`
`and
`the
`the
`
`drug-free.
`2.9% when
`is much
`latter
`figure
`normal
`subject
`after
`
`is
`
`It
`closer
`par-
`
`l000
`
`while
`011
`noteworthy
`in
`found
`to
`that
`administration.
`enteral
`of
`the
`Atialysis
`by
`ethyl
`(cid:1)omplished
`dilution
`isotol)e
`verse
`which
`studies
`all
`the
`intravenously,
`ble.
`A representative
`subject
`JA is
`recorded
`the
`initial
`sample
`but
`that
`thereafter
`greater
`percentage
`sumably
`conj
`ugated
`been
`plotted
`graphically
`contrast
`to
`those
`in
`differentiated
`l)lasma
`analysis
`the
`
`ill
`
`after
`
`oral
`
`ac-
`was
`radioactivity
`plasma
`:tlid me-
`extraction
`acetate
`naloxoite.
`In
`carrier
`with
`was
`given
`antagonist
`the
`compara-
`were
`closely
`results
`values
`obtained
`with
`of
`set
`table
`2 and
`shows
`that
`in
`mostly
`of
`con.sists
`Ilaloxolle
`progressively
`contains
`nonextractal)le
`amid
`of
`material.
`These
`results
`figure
`3 Illid
`1 which
`record
`figure
`tat-
`radioactivity.
`‘I’Iie
`plasnut
`dose
`is
`recorded
`
`a
`
`pre-
`have
`are
`
`in
`
`iii
`
`also
`
`in
`
`TABLE
`
`2
`
`A italysis
`
`of plasma
`
`radioactivity
`
`in
`
`subject
`
`JA
`
`Plasma
`
`Sample
`
`Acetate
`Ethyl
`Extract
`
`Thin-Layer
`tography
`Isotope
`
`Chroma-
`Reverse
`and
`Dilution
`
`100..
`
`.\
`
`‘2(cid:1)
`
`0
`
`10
`
`I
`
`4
`5
`ItOURS AFTER INJECTION
`
`)
`
`S
`
`4.
`
`FIG.
`intravenous
`
`naloxone-3H
`of
`i)ecay
`administration
`(subject
`
`in
`
`plasma
`JA).
`
`after
`
`the
`
`Ill
`
`this
`
`is
`
`is
`it
`extent.
`
`a
`
`i.v.
`
`86(cid:1)
`65
`42
`27
`19
`
`Oral
`
`iv.
`
`Oral
`
`83a
`68
`37
`26
`
`98h
`
`89
`84
`79
`70
`
`17b
`14
`11
`
`15 mm
`30 mm
`60 ruin
`180 ruin
`360 mm
`
`a Percentage
`h Percentage
`
`of
`of
`
`total
`ethyl
`
`plasma
`acetate
`
`radioactivity.
`extract.
`. Naloxone
`
`-
`
`.
`
`90
`
`10
`
`30(cid:1)
`
`10
`
`(cid:1)50
`
`(cid:1)-
`
`.
`
`-..
`
`Non-P4aloxone
`
`.(cid:1)
`
`I
`
`.
`
`(cid:1)-(cid:1):
`
`3
`
`2
`
`4
`
`5
`
`6
`
`3.
`
`Fia.
`naloxone
`intravenous
`
`1)isappearance
`plasma
`radioactivi
`administration
`
`HOURS
`
`of
`
`naloxone
`ty
`after
`(subject
`
`arid
`naloxone-3H
`JA).
`
`non-
`
`unie
`bolic
`veoious
`it
`niust.
`depend
`numv
`lations
`these
`unknown
`The
`venous
`
`l)e
`
`solvent-extractable
`to
`the
`intravenous
`to
`with
`lIaloXOlle
`the
`omon-nalox-
`of
`unknowom.
`It
`should
`of
`1)lttSIfliL
`ra(iiO-
`the
`above
`anal-
`of
`samples.
`The
`results
`subject
`to
`eon-
`recorded
`should
`
`(lecay
`
`l)lasli(cid:1)a
`ion all
`
`ill
`in
`
`little
`of
`the
`volume
`was
`
`of
`subject
`
`initra-
`JA,
`
`case
`(olnjnorahle
`associated
`nature
`‘l’he
`is at
`present
`rapid
`accuracy
`the
`later
`are
`therefore
`values
`the
`context.
`of
`time
`vs.
`intraveoiously,
`fitted
`l(cid:1)’
`
`the
`the
`
`ill
`
`and
`this
`in
`logarithm
`J)l(Jtted
`given
`be
`
`2.
`table
`radioactivity
`studies,
`i)Ut.
`lesser
`much
`ra(lioact.ivity
`One
`hti(cid:1)((cid:1)55((cid:1)(l
`that
`be
`activity
`limits
`\‘ses
`I)art.ieularlY
`in
`tlWse
`samples
`siderable
`error
`be
`colisidered
`con-
`naloxone
`\Vheim
`the
`where
`studies
`centration
`is
`the
`disappear-
`\v:ts
`imaloxone
`straight
`line
`after
`a
`(()tll(l
`atice
`rate
`a
`one-compart-
`with
`hour,
`the
`first
`collsiSt.ellt
`curve
`is
`1)resellted
`A iepreseoita.ti(cid:1)’e
`irmodel.
`it
`flWl
`figure
`4, with
`the
`extral)olate(l
`iomtereept
`in
`y
`Analysis
`(lesigliated
`by
`the
`dashed
`line.
`of
`these
`the
`a(cid:1))parent
`data
`pernutte(l
`calculation
`of
`(cid:1)‘ol-
`dist
`ribtition,
`l)lasnut
`half-t
`in(cid:1)e
`and
`meta-
`of
`clearance
`rates
`of
`naloxomie
`the
`intra-
`all
`studies.
`‘l’hese
`are
`listed
`table
`3 and
`l)e
`cautiooied
`that
`since
`these
`values
`laogely
`on
`the
`later
`J)litSIiiit
`samples
`they
`hIll)ject
`to
`eolisi(lerable
`error.
`No
`ealcu-
`recorded
`for
`the
`oral
`study
`since
`tle
`have
`significance
`in view
`of
`the
`would
`oiature
`j )lasma
`radioactivity.
`a(cid:1))parent
`of
`distribution
`omaloxone
`230
`liters
`in
`
`Page 4
`
`(cid:1)
`(cid:1)
`

`

`1973
`
`DISPOSITION
`
`OF
`
`NALOXONE
`
`IN MAN
`
`579
`
`in
`was
`it
`subject
`liters
`165
`compared
`half-life
`l)lasma
`The
`90 minutes,
`was
`patient
`it was
`only
`70 minutes
`rates
`clearance
`2550
`liters/day,
`the
`two
`
`FR
`to
`
`while
`heroin
`drawal.
`JA
`ject
`dependent
`arid
`heroin
`metabolic
`The
`at.
`2340
`high
`differences
`rected
`
`for
`
`to
`between
`body
`area.
`
`the
`
`when
`liters
`250
`opiate
`after
`naloxone
`of
`in
`while
`100 minutes
`when
`were
`wit.h
`subjects
`
`on
`with-
`sub-
`in
`opiate
`when
`opiate-free.
`uniformly
`only
`small
`when
`cor-
`
`on
`
`TABLE
`
`3
`
`of
`Pharm,acokinetics
`are:
`used
`Abbreviations
`naloxone;
`of
`distribution
`concentration
`any
`plasma
`MCR,
`volume
`by
`50%;
`is
`completely
`naloxone
`MCR/m’,
`in
`time;
`unit
`per
`square
`meter
`of
`
`skin
`
`intra
`
`\‘D,
`
`of
`of
`
`venous
`apparent
`T112,
`time
`naloxone
`blood
`irreversibly
`and
`metabolic
`clearance
`area.
`
`of
`
`(cid:1)ie
`naloxo
`volume
`in
`which
`is
`reduced
`from
`which
`removed
`mate
`
`(cid:1)A
`
`FR on
`Heroin
`
`Nar-
`FR
`cotic-Free
`
`(liters)
`\D
`T112 (miii)
`MCII
`(liters/day)
`MCR/m
`(liters/day)
`
`230
`90
`2550
`1270
`
`250
`100
`2540
`1450
`
`165
`70
`2340
`1330
`
`of
`
`in
`
`suggest
`from
`through
`oral
`activity
`tract
`does
`
`the
`counts,
`sufficient
`or Products
`Product
`study.
`The
`this
`protection
`that
`transformation
`the
`liver
`since
`not
`
`nature
`could
`present
`of
`the
`during
`lead
`
`this
`he
`
`of
`not
`experi-
`naloxone
`its
`first
`to more
`from
`the
`constitute
`
`to
`
`would
`absorption
`appear
`
`lack
`the
`transformation
`determined
`ments
`molecule
`transport
`effective
`intestinal
`the
`problem.
`the
`in
`The
`differences
`administered
`naloxone
`when
`those
`obtained
`heroin
`with
`some
`interest.
`of
`dmawal
`are
`not
`pharmacological
`given
`was
`not
`hence
`withdrawal
`effects
`were
`any
`is
`an
`isolated
`study
`and
`great
`should
`be
`considered
`with
`that
`be
`significant.,
`however,
`opiate-free
`values
`obtained
`in
`the
`differences,
`corrected
`for
`body
`weight
`fommly
`closer
`to
`those
`obtained
`in
`subject
`than
`those
`obtained
`was
`heroin.
`Thus
`the
`of
`liters
`the
`63-kg
`in
`with
`230-liter
`volume
`
`of
`l)harmacokinetics
`with
`coincidentally
`with-
`after
`opiate
`The
`dose
`of naloxone
`( < 5
`jig)
`and
`involved.
`This
`generalization
`caution.
`It may
`the
`calculated
`study,
`when
`uni-
`are
`normal
`the
`subject
`the
`distribution
`of
`compares
`better
`81-kg
`normal
`
`while
`
`volume
`addict
`of
`
`the
`
`on
`165
`
`a
`
`a value
`patient
`70 minutes
`value
`T,12
`than
`the
`90 minutes
`when
`these
`heroin
`oil
`weight
`differences.
`The
`similar
`intravenous
`logical
`FR
`free
`administered
`
`thaii
`
`of
`
`of
`
`liters.
`250
`closer
`is
`100-minute
`are
`
`Similarly
`to
`the
`value
`adjusted
`
`the
`normal
`obtained
`for
`body
`
`dose
`
`obtained
`results
`which
`in
`(cid:1)g was
`given
`iii
`which
`that
`
`study
`of
`125
`experiment
`suggests
`
`a
`
`from
`near
`and
`only
`comparable
`
`the
`
`.JA
`
`the
`Pharlimco-
`narcotic-
`j(cid:1)g
`were
`values
`
`4
`
`Discussion
`
`from
`
`in
`
`of
`reason
`
`these
`evident
`from
`cleared
`of
`administration.
`is
`rapidly
`excreted
`life
`is
`of
`duration.
`short
`and
`pharmacological
`be
`connected,
`transfer
`is
`the
`sufficient
`to
`naloxone.
`of
`actioni
`calculated
`of
`naloxone
`its
`observed
`with
`well
`of 3 to
`4 hours.
`The
`half-life
`of morphine
`1972)
`showed
`it
`that
`of
`naloxone
`action
`duration
`of
`of
`large
`volume
`the
`small
`percentage
`when
`considered
`metabolic
`clearance
`a
`l)oint
`to
`rapid
`the
`administered
`for
`its
`short
`
`obviously
`reaches
`by
`
`the
`is,
`
`of
`
`hut
`iiot
`to
`serves
`administered
`illustrates
`the
`apparently
`first
`the
`material
`is
`
`largely
`therefore
`is
`altered
`
`Sifl(e
`
`ill
`
`and
`
`absorbed
`rapidly
`is
`l)lasma
`comparable
`and
`dose.
`intravenous
`attained
`free
`not
`however,
`in
`plasma
`l)mesum-
`it which
`a metabolite
`potency
`biological
`same
`have
`the
`the
`effectiveness
`diminish
`result
`The
`oral
`material.
`tialox-
`rapid
`metabolism
`of
`nearly
`all
`of
`is metabo-
`it
`transit.
`It
`is noteworthy
`hepatic
`the
`blood
`after
`entering
`extractable
`with
`not
`conjugated
`naloxone
`molecule.
`
`is
`It
`rapidly
`is
`route
`its
`material
`plasma
`concentration
`not
`necessarily
`a
`blood-brain
`are
`obtained
`duration
`hour
`4
`plasma
`life
`the
`studies
`corresponds
`macological
`lifetime
`reported
`plasma
`(Spector
`and
`Vesell,
`stantially
`longer
`than
`resl)oncls
`to
`the
`greater
`narcotic
`agonist.
`The
`tion
`naloxone
`and
`of
`dose
`present
`plasma
`junction
`with
`the
`high
`and
`excretion
`urinary
`tensive
`metabolism
`as
`the
`PriliciPal
`action.
`dose
`oral
`The
`blood
`the
`into
`that
`to
`levels
`material
`The
`naloxoome,
`ably
`does
`and
`hence
`the
`orally
`further
`one
`lized
`the
`that
`naloxotie
`solvent
`structurally
`
`the
`
`studies
`body
`The
`in
`
`of
`
`its
`
`iialoxone
`that
`irrespective
`administered
`urine
`and
`While
`plasma
`l)otencY
`need
`particularlY
`when
`involved,
`the
`results
`explain
`short
`3 to
`of
`Indeed,
`in
`these
`pham-
`recently
`in man
`be
`sub-
`and
`cor-
`this
`of
`distribu-
`of
`
`to
`
`in
`
`the
`con-
`rate
`ex-
`
`and
`material
`duration
`
`of
`
`of
`
`oral
`organic
`but
`is
`Due
`
`a
`to
`
`Page 5
`
`(cid:1)
`

`

`580
`
`FISHMAN
`
`ET
`
`AL.
`
`be
`would
`of naloxone
`
`obtained
`(> 400
`
`from
`(cid:1)tg).
`
`a pharmacological
`
`dose
`
`References
`H. B.,
`GEORGE,
`DAYTON,
`N.
`: N-allylnoroxymomphone:
`antagonist.
`Fed.
`Proc.
`
`H.,
`
`D.
`narcotic
`
`M.
`
`20:
`
`AND
`
`A
`311,
`
`J.
`
`of naloxone-3-glucuro-
`Proc.
`Soc.
`Exp.
`
`Vol.
`
`187
`
`Biol.
`
`: Isolation
`?(cid:1)I.
`FuJI(cid:1)1oTo,
`human
`urine.
`from
`nide
`Med.
`133: 317-319,
`1970.
`W. H.
`D.
`II.,
`JA5IN5KI,
`MARTIN,
`pharmacology
`: The
`human
`A.
`C.
`of N-allylnoroxymorphone
`potential
`Exp.
`Them.
`157:
`J. Pharmacol.
`E.
`S.
`SPECTOR,
`VESELL,
`AND
`in man.
`Science
`morphine
`421-422, 1972.
`S. H.,
`WEINSTEIN,
`L.
`INDINOLI,
`AND
`naloxone
`in
`human
`1567-1568,
`1971.
`A.,
`ZAKS,
`JAMES,
`A. M.:
`Naloxone
`ence.
`J. Amer.
`
`AND
`
`HAERTZEN,
`and
`abuse
`(naloxone).
`1967.
`
`of
`174:
`
`420-426,
`S.
`: Disposition
`(Washington)
`
`PFEFFER,
`MINTZ,
`urine.
`
`M.,
`M.
`J.
`
`SCHOR,
`: Metabolites
`Pharm.
`
`J. M.,
`of
`60:
`
`Sci.
`
`T.,
`
`Med.
`
`FINK,
`treatment
`Ass.
`
`M.
`
`215:
`
`AND
`opiate
`of
`2108-2110,
`
`FREEDMAN,
`depend-
`1971.
`
`BLUMBERG,
`RAPAPORT,
`potent
`1961.
`FI5HMAN,
`Preparation
`7,8-(cid:1)H.
`FOLDES,
`BROWN,
`potent
`245:
`
`J.,
`
`B.:
`
`J.
`AND
`A new
`Sci.
`
`J. Med.
`
`L.
`M.
`NORTON,
`AND
`COTTER,
`of naloxone-
`stability
`and
`biological
`1973.
`556-557,
`16:
`J. Med.
`Chem.
`N.,
`J.
`F.
`F.,
`MOORE,
`LUNN,
`I. M.:
`N-allylnomoxymorphone:
`narcotic
`antagonist.
`Amer.
`23-30,
`1963.
`
`Page 6
`
`