THE
`
`SECRETION
`GASTRIC
`A (cid:1)H
`PARTITION
`
`OF
`HYPOTHESIS’
`
`DRUGS:
`
`PARKHURST
`
`SHORE,
`A.
`C. ADRIAN
`
`BERNARD
`M. HOGBEN
`
`B. BRODIE
`
`AND
`
`Laboratory
`National
`
`of Chemical
`Heart
`Department
`
`of Kidney
`Laboratory
`and
`Pharmacology
`Institutes
`of Health,
`Public
`Institute,
`National
`of Health,
`Education,
`and Welfare,
`Bethesda,
`
`Electrolyte
`and
`Health
`Service,
`Maryland
`
`Metabolism,
`U.
`S.
`
`Received
`
`for
`
`publication
`
`Sept.
`
`5,
`
`1956
`
`compounds
`foreign
`generally
`ignored
`have
`reported
`the
`administration.
`A number
`the
`by
`the
`gastric
`mucosa
`of
`Dawson
`and
`Ivy,
`1925;
`Ingraham
`1954).
`There
`are
`a number
`et al.,
`the
`gastric
`juice
`but
`other
`the
`data
`of various
`investigators
`its
`gastric
`transfer
`except
`in
`in
`low concentration
`and Way
`(1954),
`in studying
`in
`the
`rat,
`found
`rather
`
`juice
`gastric
`into
`pharmacologists
`by
`of
`organic
`presence
`of workers
`have
`dog,
`while
`acidic
`Visscher,
`stating
`in
`are
`concluded
`and
`Davenport
`traces.”
`juice
`after
`gastric
`of parenter-
`fate
`amounts
`of
`
`and
`reports
`of
`reports
`
`in
`the
`the
`large
`
`is a route
`and
`in
`
`bases
`shown
`dyes
`1935;
`that
`conflict.
`that
`
`the
`
`and
`
`are
`
`other
`of drugs
`secretion
`The
`has
`been
`which
`disposition
`drug
`of
`investigators
`Various
`toxicologists.
`parenteral
`after
`the
`stomach
`secreted
`dyes
`that
`basic
`1926;
`are
`not
`(Kobayashi,
`Cambel
`Ray
`1953;
`et al.,
`into
`morphine
`is
`secreted
`reviewed
`Sumwalt
`(1941)
`has
`work
`denies
`“the
`available
`best
`sulfonamides
`(1942)
`found
`certain
`Sung
`parenteral
`administration.
`ally
`administered
`acetylmethadol
`drug
`in
`the
`stomach
`contents.
`Our
`own
`interest
`secretion
`gastric
`in
`intravenously
`levorphan
`(Dromoran)
`juice
`high
`concentration
`(Shore
`present
`paper
`describes
`gastric
`of heterogeneous
`structure
`and
`shows
`organic
`electrolytes
`is
`dependent
`results
`the
`formulation
`gastric
`that
`is
`in
`accord
`
`of
`
`in
`
`the
`
`The
`and
`
`blood
`
`allow
`juice
`
`that
`gastric
`The
`drugs
`weak
`compound.
`tween
`
`was
`drugs
`administered
`1955a).
`et
`al.,
`secretion
`of a variety
`that
`extent
`the
`upon
`ionization
`the
`a model
`of
`experimental
`
`instigated
`to
`
`by
`dogs
`
`observation
`the
`appeared
`in
`
`the
`
`acidic
`
`of
`the
`be-
`
`a
`
`barrier
`
`and
`of basic
`secretion
`of gastric
`constant
`of
`lipoid
`data.
`
`of
`with
`
`The
`methods.
`AND MATERIALS.
`METHODS
`the
`for
`employed
`methods
`described
`previously
`been
`have
`materials
`in
`compounds
`the
`various
`of
`exception
`of p-hydroxypropiophenone;
`and
`Axeirod,
`(Brodie
`aniline
`and
`acetanilide
`antipyrine
`1952);
`Reichenthal,
`and
`theophylline
`(Brodie,
`Axeirod
`al.,
`et
`(Brodie
`(Josephson
`1950);
`quinine
`aminopyrine
`(Brodie
`and
`Axeirod,
`al.,
`et
`1947);
`levorphan
`and Axeirod,
`(Brodie,
`Aronow
`Dromoran)
`(Shore
`1955);
`tolazoline
`(Priscoline)
`et al.,
`1951);
`phenylbutazone
`1944);
`probenecid
`(Beyer
`et at.,
`et al.,
`acid
`salicylic
`(Brodie
`1950);
`1953);
`thiopental
`et at.,
`(Brodie et al,
`and barbital
`(Goldbaum,
`(Burns
`lidin)
`The
`compound
`was
`extracted
`p-Hydroxypropiophenone
`was
`estimated
`as
`follows:
`benzene.
`An
`aliquot
`of
`the
`acidified
`plasma
`or
`juice
`into
`five
`volumes
`of
`phase
`then
`shaken
`2.5 N sodium
`hydroxide,
`and
`the
`optical
`density
`of
`the
`
`Analytical
`biological
`
`was
`
`gastric
`with
`
`estimation
`with
`
`I he
`1948);
`1949);
`
`(1-
`1952);
`(Butazo-
`1948).
`from
`benzene
`alkaline
`
`‘A
`
`preliminary
`
`report
`
`on
`
`this
`
`work
`
`was
`
`presented
`
`before
`
`the
`
`American
`
`Society
`
`for
`
`Pharmacology
`
`and
`
`Experimental
`
`Therapeutics,
`
`Atlantic
`
`City,
`
`N.
`
`J.,
`
`April,
`
`1954.
`
`361
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`362
`
`SHORE,
`
`BRODIE
`
`AND
`
`HOGBEN
`
`phase
`
`measured
`
`to
`
`a Beckman
`were
`satisfactory
`constants.
`have
`
`3
`
`Recoveries
`cent).
`per
`reported
`in
`
`of
`
`the
`
`drug
`
`added
`
`for
`
`spectrophotometer.
`at 325 mM with
`(95
`±
`gastric
`juice
`and
`plasma
`constants
`dissociation
`most
`Since
`of dissociation
`Determination
`drugs
`used
`the
`systems,
`partially
`nonaqueous
`beeii
`determined
`these
`experimessts
`in
`methods
`ionic
`strength.
`Several
`medium
`of constant
`aqueous
`were
`redetermined
`in an
`they
`acetanilide,
`quinine,
`theophylline,
`aminopyrine,
`levorphan,
`used.
`The
`pKa
`values
`of
`were
`between
`an
`organic
`solvent
`determined
`by
`distribution
`and
`probenecid
`were
`antipyrine
`The
`spectrophotometric
`by Butler
`(1953).
`described
`various
`pH
`as
`values
`of
`buffers
`(1935)
`thiopental,
`barbital,
`Hammett
`Dingwall
`was
`for
`and
`of Flexser,
`For
`and
`phenylbutazone.
`both
`methods
`the
`drugs
`were
`propiophenone
`0.1 M saline
`Microtitration
`in
`0.1 M buffer.
`for
`tolazoline,
`aniline
`acid.
`All
`values
`as
`pKa.
`are
`expressed
`extent
`proteins.
`to plasma
`Determination
`of drug
`binding
`proteins
`are
`bound
`the
`appropriate
`plasma
`concentration
`at
`with
`the
`methods,
`lished
`in
`the
`references
`to
`analytical
`, p-hydroxypropiophenone,
`aniline,
`quinine,
`levorphan,
`antipyrine
`cent
`extent
`of
`about
`75 per
`phylline.
`Salicylic
`acid
`is bound
`to
`the
`values
`the
`other
`compounds
`were
`determined
`by
`the
`ultrafiltration
`1.
`(1943)
`are
`listed
`in
`table
`several
`used
`pouch
`fundic
`Heidenhain
`denervated
`Dogs,
`of either
`sex, with
`a vagally
`for
`about
`were
`fasted
`after
`operation.
`The
`animals
`experi-
`each
`prior
`16 hours
`weeks
`a super-
`into
`intravenously
`infused
`cent
`saline,
`ment.
`Histamine,
`dissolved
`in 0.9
`was
`pump,
`and
`infusion
`a Bowman
`hour,
`using
`kgm.
`per
`ficial
`leg
`vein
`a rate
`of 0.25 mgm.
`at
`rate
`of histamine
`in-
`the
`experimental
`period.
`This
`the
`infusion
`continued
`throughout
`was
`and
`acidity
`of gastric
`juice
`(Obrink,
`1948). When
`the
`fusion
`elicits
`a maximal
`secretory
`rate
`under
`juice
`flowing
`freely
`through
`cannula,
`a priming
`dose
`of
`the
`drug
`investigation
`was
`of
`the
`was
`intravenously
`followed
`by
`a constant
`intravenous
`infusion
`drug
`to main-
`injected
`dose
`tain
`a
`relatively
`constant
`blood
`level.
`Only
`priming
`of probenecid
`and
`the
`bar-
`biturates
`drugs
`necessary
`the
`plasma
`levels
`these
`declined
`at
`a sufficiently
`slow
`of
`was
`one-half
`rate
`following
`a single
`After
`waiting
`about
`hour
`ensure
`approximate
`equilibrium
`body,
`distribution
`drug
`throughout
`the
`simultaneous
`gastric
`juice
`hour
`venous
`(jugular)
`blood
`were
`taken.
`another
`one-half
`the
`sampling
`After
`were
`repeated.
`The
`concentrations
`drug
`in
`and
`in
`gastric
`juice
`determined
`of
`plasma
`the
`values
`expressed
`as
`concentration
`R,
`that
`is,
`concentration
`of
`ratio,
`gastric
`juice
`divided
`by
`concentration
`in
`plasma.
`
`above
`
`for
`and
`
`used
`these
`used
`
`was
`
`The
`to
`
`and
`method
`p-hydroxy-
`dissolved
`and
`salicylic
`
`in
`
`various
`the
`to which
`previously
`has
`been
`of
`salicylic
`exception
`probenecid
`and
`(Smith
`et at.,
`1947).
`technique
`of Rehberg
`
`drugs
`pub-
`acid,
`theo-
`The
`
`were
`to
`
`per
`per
`
`the
`
`the
`
`since
`injection.
`of
`the
`samples
`
`the
`the
`
`to
`
`the
`
`and
`was
`and
`in
`
`drug
`
`concentration
`The
`experimental
`summarizes
`with
`increasing
`R increased
`for
`compounds
`with
`a pKa
`of pKa
`above
`no
`effect
`5 had
`as
`R value
`the
`stronger
`much
`repeatedly
`confirmed,
`
`the
`
`to
`
`shown
`drug
`each
`for
`ratio
`for
`evident
`is
`It
`findings.
`value
`a limiting
`until
`basicity
`stronger
`For
`these
`of 5 or higher.
`(pKa
`on R.
`For
`example,
`aniline
`Tolazoline
`base
`levorphan
`(pKa
`9.2).
`the
`otherwise
`striking
`constancy
`
`(R)
`
`is
`that
`
`in table
`the
`basic
`of
`about
`bases,
`5)
`had
`was
`of R for
`
`average
`
`RESULTS.
`1, which
`compounds,
`40 was
`reached
`an
`increase
`the
`same
`an
`exception,
`stronger
`bases.
`The
`concentration
`as
`Strong
`acids
`such
`4.4
`ranging
`from
`3 to
`acids
`p-hydroxypropiophenone,
`A possible
`explanation
`
`ratios
`salicylic
`could
`
`not
`
`acids
`the
`for
`probenecid
`acid,
`detected
`be
`thiopental
`limiting
`
`with
`increased
`and
`phenylbutazone
`the
`gastric
`juice,
`in
`barbital
`were
`and
`concentration
`ratio
`cleared
`from
`blood
`
`also
`
`the
`
`pKa.
`increasing
`pKa’s
`with
`the weaker
`while
`secreted.
`stronger
`they
`pass
`
`bases
`through
`
`all
`for
`as
`
`is
`
`the
`for
`completely
`
`that
`
`these
`
`compounds
`
`are
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`GASTRIC
`
`SECRETION
`
`OF
`
`DRUGS
`
`TABLE
`secretion
`
`1
`of drugs
`
`Gastric
`
`Drug
`
`Bases
`
`Acetanilide
`Theophylline
`Antipyrine
`Aniline
`Aminopyrine
`Quinine
`Levorphan
`Tolazoline
`
`Acids
`acid
`
`Salicylic
`Probenecid
`Phenylbutazone...
`p-Hydroxypropio-
`phenone
`Thiopental
`Barbital
`
`Plasma
`protein
`
`binding
`
`pKa
`
`.
`.
`Priming
`dose
`
`.
`Infusion
`dose
`
`mgrn./
`kgm.
`33
`30
`66
`20
`20
`50
`2
`15
`
`mgm./
`kgm/hr.
`66
`30
`66
`10
`10
`24
`1
`5
`
`75
`25
`30
`
`17
`44
`200
`
`38
`
`-
`
`10
`
`9
`
`-
`
`-
`
`0.3
`0.7
`1.4
`5.0
`5.0
`8.4
`9.2
`10.3
`
`3
`3.4
`4.4
`
`7.8
`7.6
`7.8
`
`‘(cid:1)
`0
`15
`0
`25
`15
`75
`50
`23
`
`75
`75
`90
`
`75
`75
`0
`
`concentrations
`and Drug
`concentrations
`Drug
`R value at one-half hour
`R value at one
`
`and
`hour
`
`Pbs-
`ma’
`
`Gastric
`juice
`
`R
`
`Gastric
`juice
`
`R
`
`-(cid:1)
`
`Plas-
`ma’
`
`mgm./
`i(cid:1)
`126
`81
`230
`8.5
`24
`4.7
`0.2
`13.2
`
`mgm./l.
`126
`118
`938
`358
`1010
`189
`8.3
`135
`
`mgm./l.
`
`78
`81
`575
`350
`1050
`144
`7.8
`125
`
`1
`1.5
`4.2
`38
`42
`36
`39
`11
`
`mgm./
`1.
`78
`54
`138
`9.5
`25
`4.0
`0.2
`12.0
`
`270
`14
`185
`
`0
`0
`0
`
`0
`0
`0
`
`338
`14
`195
`
`0
`0
`0
`
`6.4
`23
`268
`
`0.95
`3.2
`164
`
`0.15
`0.14
`0.6
`
`5.5
`20
`254
`
`0.62
`2.0
`152
`
`1
`1.5
`4.1
`42
`42
`40
`42
`10
`
`0
`0
`0
`
`0.11
`0.10
`0.6
`
`* Plasma
`
`values
`
`represent
`
`total
`
`(bound
`
`+
`
`unbound)
`
`drug.
`
`363
`
`Aver
`age
`R
`value
`
`1
`1.5
`4.2
`40
`42
`38
`40
`10.5
`
`0
`0
`0
`
`0.13
`0.12
`0.6
`
`gastric
`the
`stomach
`The
`cardiac
`the
`cannulated
`short
`length
`mine
`were
`
`copious,
`
`jugular
`whole
`data
`blood
`blood
`that
`lowed
`plasma
`the
`all
`of
`This
`hum.
`from
`blood
`Accordingly,
`was
`complete
`
`following
`the
`tested
`was
`hypothesis
`epithelium.
`at
`anesthesia
`pentobarbital
`under
`dog
`of
`a normal
`were
`a gastro-epiploic
`vein
`and
`jugular
`The
`and
`pyloric
`with
`itself
`was
`cannulated
`stomach
`The
`tubing.
`with
`polyvinyl
`hista-
`and
`with
`saline.
`Aniline
`flushed
`clean
`and
`of
`rubber
`tubing
`was
`juice
`of
`the
`flow
`gastric
`above.
`When
`described
`administered
`as
`of
`samples
`hour,
`simultaneous
`for
`one-half
`infused
`aniline
`been
`had
`and
`of
`content
`taken.
`The
`aniline
`were
`blood
`venous
`and
`gastro-epiploic
`blood
`the
`Table
`2 summarizes
`was measured.
`sample
`and
`plasma
`of
`blood
`whole
`the
`aniline
`in
`the
`of
`64
`per
`cent
`about
`indicates
`and
`obtained
`from
`The
`aniline
`removed
`the
`stomach.
`through
`by
`passage
`removed
`was
`appear
`plasma.
`Thus
`it might
`in
`the
`present
`was
`originally
`than
`was more
`fol-
`red
`cells
`were
`cleared
`of
`aniline,
`of
`the
`and
`a portion
`plasma
`all
`of
`the
`of
`equilibrium
`of
`drug
`between
`the
`rapid
`reestablishment
`by
`a subsequent
`likely
`possibility,
`however,
`is
`that
`alternative
`and more
`An
`and
`red
`cells.
`blood
`serving
`gastric
`epithe-
`the
`completely
`cleared
`from
`drug
`was
`the
`is not
`unreasonable
`since
`gastro-epiploic
`venous
`sample
`represents
`the
`not
`only
`the
`epitheium
`also
`the
`wall
`and
`anastomoses.
`but
`muscle
`two-thirds
`of
`the
`contacted
`the
`epithelium
`where
`clearance
`and
`the
`remaining
`passed
`through
`the muscle
`arterio-
`
`by
`
`experiment.
`was
`ligated
`vein
`
`a
`
`This
`male
`ends.
`
`was
`
`each
`that
`
`blood
`one-third
`
`and
`
`TEVA EXHIBIT 1024
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`364
`
`SHORE,
`
`BRODIE
`
`AND
`
`HOGBEN
`
`venous
`clearance
`
`anastomoses
`of
`substances
`
`where
`by
`
`no
`the
`
`removal
`epithelium
`
`of
`
`drug
`would
`
`would
`explain
`
`take
`the
`
`place.
`apparent
`
`Complete
`limit
`
`of
`
`ratios
`The
`varying
`
`of
`
`concentration
`
`DIscusSIoN.
`sess
`greatly
`with
`a diversity
`the
`compounds
`is
`the
`result
`actions.
`From
`that
`changes
`compounds.
`pKa
`of
`This
`juice
`across
`centration
`brane.
`equilibrium
`markedly,
`
`bases
`pK
`
`of
`However,
`with
`the
`
`the
`that
`used
`weak
`dissociation
`structures
`effects.
`pharmacologic
`of
`gastric
`the
`secreted
`into
`transport
`an
`“active”
`the
`data
`summarized
`the
`consistently
`with
`Except
`for
`stronger
`the
`and
`acids
`results
`in
`dependence
`may
`explained
`be
`by
`separated
`are
`a membrane
`having
`the
`which
`only
`undissociated
`molecule
`undissociated
`drug
`would
`be
`in gastric
`juice
`and
`plasma
`the
`ionized
`moiety.
`Since
`concentration
`of
`ionized
`drug
`
`secreted.
`are
`secretion
`gastric
`of
`compounds
`include
`and
`structures
`of
`chemical
`The
`this
`secretion
`it unlikely
`that
`juice
`chemical
`involving
`specific
`mechanism
`only
`variable
`is apparent
`that
`the
`in table
`lit
`observed
`concentration
`ratio
`is the
`pKa
`of
`pKa>
`bases,
`those
`with
`5,
`an
`increase
`in
`increased
`concentration
`ratio.
`and
`by
`concept
`plasma
`characteristics
`of
`a lipoid
`can
`pass.
`equilibrium,
`lipoid
`both
`sides
`of
`a
`equal
`on
`the
`unionized
`moiety
`must
`also
`the
`pH
`the
`two
`phases
`may
`markedly
`in
`
`when
`occurs
`electrolytes
`and
`
`bases
`stronger
`study
`in
`the
`constants
`diversity
`makes
`
`an
`
`the
`the
`
`that
`
`At
`
`of
`differ
`
`pos-
`
`of
`
`re-
`
`the
`the
`
`gastric
`barrier,
`the
`con-
`mem-
`be
`differs
`two
`
`the
`
`in
`
`phases,
`
`the
`
`difference
`
`depending
`
`on
`
`the
`
`figure
`
`1,
`
`the
`
`gastric
`
`juice
`
`of
`
`the
`
`a pH
`
`of
`
`If,
`
`of
`
`matically
`
`in
`
`pKa
`has
`
`drug.
`1 and
`
`as
`the
`
`pictured
`plasma
`
`with
`
`an
`
`oil
`
`layer
`
`separating
`
`the
`
`two,
`
`parenterally
`
`administered
`
`bases
`
`diagram-
`a pH
`would
`
`7
`be
`
`Clearance
`
`of
`
`TABLE
`aniline
`
`by
`
`2
`the
`
`gastric
`
`inucosa
`
`Systemic
`
`Blood
`
`Gastric
`
`Blood
`
`Hematocrit
`Aniline
`Aniline
`Calculated
`blood
`
`per ml.)...
`(microgm.
`cone.
`blood
`whole
`(microgm.
`per ml.)
`cone.
`plasma
`of 1 ml.
`aniline in plasma
`
`whole
`
`0.54
`16.8
`15.9
`
`7.3
`
`0.53
`6.0
`5.8
`
`2.8
`
`PLASMA
`pH?
`
`F(cid:1)OILA
`
`GASTRIC
`
`JUICE
`
`pH I
`
`41
`
`UNIONIZED
`
`tI(cid:1)tI
`
`IONIZED
`
`UNIONIZED
`
`IONIZED
`
`1. Model
`
`illustrating
`
`pH partition
`
`mechanism
`
`of gastric
`
`secretion
`
`of weak
`
`electro-
`
`FIG.
`lytes.
`
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`

`
`GASTRIC
`
`SECRETION
`
`OF
`
`I)RUGS
`
`365
`
`be
`on
`
`to
`
`expected
`concentrated
`It
`is possible
`tration
`ratios
`
`the
`
`gastric
`
`on
`concentrated
`side.
`the
`plasma
`which
`to derive
`a formula
`which
`should
`theoretically
`
`juice
`
`side
`
`while
`
`acids
`
`would
`
`remain
`
`will
`obtain
`
`express
`at
`
`mathematically
`equilibrium2.
`
`the
`
`concen-
`
`R(for
`
`bases)
`
`=
`
`-
`
`R is
`where
`acid
`of
`the
`be
`calculated.
`
`theoretical
`the
`dissociation
`
`concentration
`constant
`for
`
`each
`
`1 +
`
`10(pKa-1)
`
`+
`
`1#{216}(pKa-7)
`
`1
`1 +
`
`ratio,
`drug.
`
`10(1-pKa)
`
`10(7-pKa)
`
`and
`Thus
`
`pKa
`if
`
`is
`the
`
`the
`pKa
`
`negative
`is known,
`
`logarithm
`R may
`
`2 Let U and
`scripts
`g and
`balch
`equation
`
`concentrations
`I be
`p indicate
`juice
`gastric
`for
`a base we have
`
`of unionized
`and
`plasma
`
`ionized
`and
`respectively.
`
`moieties
`From
`
`and
`respectively
`the Henderson-Hassel-
`
`sub-
`
`pH
`
`=
`
`pKa
`
`+
`
`log U/I
`
`or
`
`I
`
`=
`
`U.lO(cid:1)”
`
`-
`
`pH)
`
`The
`
`concentration
`
`ratio,
`
`Thus
`
`R -
`
`-
`
`U(cid:1)
`Up
`
`+
`+
`
`I(cid:1)
`Ip
`
`U,
`
`+
`
`R -
`
`it
`
`but
`plasma
`
`is postulated
`become
`
`equal,
`
`that
`or
`
`the
`
`concentration
`
`-
`
`+
`
`of
`
`the
`
`unionized
`
`moieties
`
`in
`
`gastric
`
`juice
`
`and
`
`thus
`
`when
`
`then
`
`U,
`
`=
`
`Up
`
`R
`
`-
`
`-
`
`1
`
`1
`
`+
`
`+
`
`1O(pK*pH2)
`10(pKapiip)
`
`pH,
`
`=
`
`1 and
`
`pH(cid:1)
`
`=
`
`7
`
`R -
`
`-
`
`1 +
`1 +
`
`10(pKft(cid:1))
`10(pKa7)
`
`A comparable
`balch
`equation
`
`equation
`for
`a weak
`
`for
`acid,
`
`an
`
`acid
`
`is obtained
`
`from
`
`the
`
`form
`
`of
`
`the
`
`Henderson-Hassel-
`
`pH
`
`=
`
`pKa
`
`+
`
`log
`
`I/Il
`
`of
`
`reason
`For
`moieties.
`ionized
`a polyvalent
`Quantitative
`been
`considered
`Orloff
`and
`Berliner,
`
`simplicity
`It must
`compound
`aspects
`previously
`1956;
`
`be
`of
`of
`
`distinction
`the
`recognized,
`large
`molecular
`the movement
`(Osterhout,
`Hogben,
`
`1954).
`
`has
`however,
`weight
`of weak
`1925;
`Jacobs,
`
`between
`drawn
`been
`dissociation
`that
`result
`may
`electrolytes
`1940;
`
`a
`in
`across
`Clowes,
`
`ionized
`the
`ionizable
`of an
`lipoid-soluble
`cell membranes
`Keltch
`and Krahl,
`
`tin-
`of
`
`and
`group
`ion.
`
`have
`1940;
`
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`(cid:1)
`

`
`366
`
`SHORB,
`
`BItODIE
`
`AND
`
`HOOBEN
`
`Figure
`plotted
`The
`gastric
`plasma
`plasma
`ing.
`
`ratio
`bound
`been
`In
`
`concentration
`
`ratios,
`
`calculated
`
`as
`
`above
`
`and
`
`1)
`with
`correct
`
`concentration
`being
`
`ratios
`for
`
`the
`yielded
`made
`allowance
`no
`concentration
`experimental
`the
`assumes
`no
`calculated
`ratio
`blood
`where
`flow limits
`the
`the mucosa
`may
`potentially
`the
`correction
`for
`plasma
`
`plasma
`concentration
`clear
`both
`binding
`has
`
`between
`binding
`ratio
`
`to
`for
`bind-
`
`the
`not
`
`is made
`determined
`obtained
`
`for
`
`between
`ratios,
`all
`the
`
`theoretical
`the
`corrected
`drugs,
`
`except
`
`for
`
`concentration
`plasma
`binding.
`for
`the
`stronger
`
`ratios
`An
`bases
`
`is
`
`theoretical
`of
`a graph
`2 is
`the
`pKa.
`of
`a function
`as
`(table
`initial
`observations
`plasma
`juice
`and
`systemic
`to
`protein.
`is necessary
`It
`binding
`since
`the
`theoretically
`the
`instances
`of
`stronger
`bases
`In
`between
`gastric
`juice
`and
`plasma,
`and
`unbound
`drug,
`therefore
`applied.
`a comparison
`3,
`table
`experimentally
`the
`and
`agreement
`excellent
`5).
`(pKa>
`these
`considering
`In
`by
`blood
`be
`limited
`must
`indicates
`experiment
`ance
`the mucosa.
`contacted
`blood
`stronger
`bases
`of
`the
`removal
`mucosa.
`the
`gastric
`be
`anticipated
`It may
`always
`yield
`the
`relatively
`
`stronger
`flow
`that
`
`bases,
`through
`R could
`value
`that
`
`The
`from
`
`is
`
`apparent
`it
`gastric
`the
`exceed
`not
`of
`about
`40
`portion
`the
`
`that
`epithelium.
`60
`even
`is
`compatible
`blood
`which
`
`the
`
`if
`
`upper
`The
`all
`
`limit
`aniline
`of
`the
`with
`passes
`
`of R
`clear-
`gastric
`complete
`through
`
`of
`
`that
`
`study
`constant
`
`a large
`of
`concentration
`
`number
`
`of
`
`stronger
`of 40
`
`that
`
`bases
`has
`
`will
`been
`
`not
`ob-
`
`ratio
`
`‘0’
`
`IO(cid:1)
`
`10(cid:1)
`
`Cl)
`
`4-
`
`J
`
`IO(cid:1)(cid:1)
`
`102
`
`0
`
`IO(cid:1)i
`
`02
`
`U I
`
`-C
`
`l)
`
`40
`
`Fia.
`of pKa.
`
`2. Theoretical
`
`concentration
`
`ratios
`
`for
`
`weak
`
`electrolytes
`
`plotted
`
`as
`
`a
`
`function
`
`p K0
`
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`

`
`GASTRIC
`
`SECRETION
`
`OF
`
`DRUGS
`
`367
`
`Comparison
`
`of
`
`experimental
`
`TABLE
`and
`
`3
`theoretical
`
`concentration
`
`ratios
`
`R (experimental)
`
`pKa
`
`Un
`
`Coriected
`
`R (theoretical)
`
`corrected
`
`for
`
`plasma
`
`1.0
`1.5
`4.2
`
`10(cid:1)
`10(cid:1)
`10’
`10’
`10’
`
`(If
`
`not
`limited)
`
`blood
`
`flow-
`
`10(cid:1)
`10(cid:1)
`10’
`
`(undetectable)
`(undetectable)
`(undetectable)
`0.6
`0.6
`0.6
`
`1.0
`1.3
`4.2
`
`0 0 0 0
`
`.5
`0.5
`0.6
`
`1.0
`1.5
`4.2
`40.
`42.
`38.
`40.
`10.5
`
`0 0 0 0
`
`.13
`0.12
`0.6
`
`0.3
`0.7
`1.4
`5.0
`5.0
`8.4
`9.2
`10.3
`
`3.
`3.4
`4.4
`7.8
`7.6
`7.8
`
`Drug
`
`Bases
`
`Acetanilide
`Theophylline
`Antipyrine
`Aniline
`Aminopyrine
`Quinine
`Levorphan
`Tolazoline
`
`Acids
`
`acid
`
`Salicylic
`Probenecid
`Phenylbutazone
`p-Hydroxypropiophenone
`Thiopental
`Barbital
`
`When
`is maximal.
`40. Any
`may
`exceed
`of gastric
`to
`the
`flow
`it may
`value
`of pKa,
`base
`will
`be
`so low that
`clear
`the
`plasma.
`Finally,
`is markedly
`favor
`
`in
`
`of
`
`gastric
`rate
`the
`modifies
`which
`drug
`change
`would
`juice
`that
`the
`be
`expected
`of passage
`the
`rate
`equilibrium
`if
`the
`binding,
`plasma
`
`of
`
`40
`encountered
`protein
`binding
`
`the
`in
`since
`
`case
`this
`
`of
`drug
`
`tolazoline
`is bound
`
`is
`to
`
`not
`the
`
`the
`
`above
`
`will
`
`is
`mucosal
`Again,
`concentration
`the mucosa
`for
`binding
`may
`be
`exception
`to
`
`when
`tamed
`formation
`juice
`gastric
`the
`ratio.
`the
`plasma
`across
`constant
`clearance
`The
`attributable
`extent
`Other
`compounds
`only
`the
`rier
`and
`constant.
`should
`tially
`dog,
`weak
`authors
`plasma
`
`of
`
`to
`
`secretion
`gastric
`of
`rate
`the
`ratio
`submaximal,
`relative
`flow
`blood
`critical
`a certain
`of undissociated
`to
`be
`too
`slow
`plasma
`protein
`to
`incomplete.
`of
`to
`the
`ratio
`significant
`plasma
`cent.
`25
`per
`only
`have
`investigators
`juice.
`gastric
`into
`form
`undissociated
`the
`that
`therefore
`These
`investigators
`secreted
`in measurable
`be
`undissociated
`form.
`After
`none
`could
`be detected
`in the
`acids
`are
`not
`secreted
`and
`failed
`take
`into
`account
`proteins
`(Shannon,
`1935)
`
`to
`attempted
`and
`Ingraham
`the
`compound
`of
`extent
`of
`secretion
`pointed
`out
`that
`amounts
`since
`administration
`gastric
`that
`the
`which
`
`the
`
`explain
`Visscher
`crosses
`might
`if
`this
`at
`
`of
`This
`
`the
`
`degree
`have
`
`juice.
`therefore
`high
`may
`
`secretion
`also
`(1935)
`the
`blood-gastric
`depend
`on
`the
`were
`very
`true,
`are
`blood
`they
`pH
`phenol
`intravenously
`red
`was
`interpreted
`to mean
`hypothesis
`invalid.
`of
`binding
`phenol
`of
`resulted
`in
`a gastric
`juice
`
`organic
`that
`bar-
`
`a
`
`basic
`of
`considered
`juice
`dissociation
`acids
`weak
`in
`a par-
`to
`that
`The
`to
`red
`con-
`
`is
`
`centration
`
`too
`
`small
`
`to
`
`detect
`
`by
`
`the
`
`analytical
`
`method
`
`used.
`
`Visscher
`
`(1942)
`
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`
`

`
`SHORE,
`
`BRODIE
`
`AND
`
`HOGBEN
`
`the
`that
`membrane
`charge
`(acid
`
`mechanism
`only
`in which
`is negative.
`dyes)
`while
`to
`explain
`
`the
`This
`allowing
`either
`
`fails
`
`with
`
`consistent
`pores
`constitute
`membrane
`would
`the
`passage
`presence
`
`the
`
`of
`
`an
`
`results
`the
`electro-static
`then
`prevent
`cations
`drugs
`
`of
`acidic
`
`perm-
`a
`required
`in which
`filter
`the
`entrance
`dyes).
`stomach
`
`(basic
`in
`
`the
`
`of
`
`This
`or
`
`368
`
`decided
`selective
`the
`pore
`anions
`hypothesis
`
`the
`
`that
`bases
`from
`respect
`this
`general
`
`high
`A logical
`acidic
`should
`the
`
`concentration
`consequence
`drugs
`should
`be
`absorbed
`picture
`usual
`absorption
`shows
`rapidly
`
`to
`laboratory
`absorbed
`
`with
`obtained
`ratios
`barrier
`lipoid
`the
`of
`absorbed
`rapidly
`be
`This
`only
`slowly.
`as
`the
`stomach
`of
`drugs.
`In
`accordance
`acidic
`compounds,
`from
`stomach
`
`the
`
`of
`that
`
`basic
`concept
`directly
`would
`a
`rather
`with
`
`compounds.
`in the
`given
`present
`stomach,
`the
`from
`a distinct
`represent
`inconsequential
`this
`concept,
`
`paper
`whereas
`departure
`organ
`research
`
`with
`from
`
`is
`
`if
`while
`
`soluble
`bases
`
`in
`
`juice,
`gastric
`are
`absorbed
`
`in
`
`are
`slowly
`
`(Shore
`
`et
`
`al.,
`
`Since
`contents
`determination
`
`many
`may
`
`1955b).
`commonly
`be
`of
`great
`of
`the
`nature
`
`used
`value
`of
`
`basic
`
`are
`drugs
`toxicologists
`to
`poisons,
`even
`
`nature,
`in
`in medico-legal
`when
`parenterally
`
`SUMMARY
`
`of
`
`sampling
`problems
`administered.
`
`stomach
`for
`
`the
`
`administered
`ratio
`
`are
`
`the
`in
`and
`
`in
`
`secreted
`drugs
`of
`drug
`(concentration
`depends
`dissociation
`on
`negligible
`gastric
`juice
`stronger
`amount
`concentration
`a limiting
`the
`limitation
`apparently
`
`directly
`in
`gastric
`constant
`concentration,
`bases
`in
`highest
`ratio
`of
`about
`being
`due
`
`into
`juice
`
`of
`
`by
`
`juice.
`con-
`Thus
`and
`
`gastric
`the
`divided
`drug.
`the
`acids
`weak
`concentration.
`40
`to
`1 when
`to
`complete
`
`be
`
`that
`
`Parenterally
`concentration
`The
`centration
`in
`strong
`weak
`The
`gastric
`clearance
`The
`brane
`membrane
`
`acids
`bases
`stronger
`juice
`by
`pattern
`separat.ing
`that
`
`restricting
`
`passage
`
`plasma)
`in
`appear
`in measurable
`bases
`appear
`flow
`is maximal,
`the
`gastric
`mucosa.
`can
`of drug
`secretion
`gastric
`plasma
`from
`allows
`passage
`of
`
`the
`dissociated
`
`explained
`juice
`drugs
`
`has
`in
`
`by
`the
`their
`
`concept
`the
`characteristics
`undissociated
`
`of
`
`the
`of
`form
`
`a
`
`mem-
`lipoid
`while
`
`form.
`
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