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ORAL ABSORPTION :lips: (DEFINTION (ACTIVE TRANSPORT (example (intestinal…

- - - - dependent
        
        inactive ingredient
        
        formulation variables
    - - complexation
      - ionization
        
        acid
        
        base
      - partition coefficient
        
        octanol
        
        water
      - solubility in water
  - - - colonic retention
      - gastric emptying
      - intestinal motility
      - perfusion
      - permeability
    - - Crohn's disease
      - diarrhea
      - gastric
        
        resection
        
        modification (obsesity)
      - ulcerative colitis
- - - - 6 meters in length
      - PARTS
        
        duodenum
        
        receive bile from
        
        pancreas
        
        gallbladders
        
        pH 6-7
        
        sphincter - separate stomach from intestine
        
        pancreatic enzymes to digest
        
        protein
        
        trypsin
        
        chymotrypsin
        
        carboxypeptidase
        
        carbohydrates
        
        amylase
        
        fats
        
        lipase
        
        ester
        
        esterases
        
        jejunum
        
        drug absorption site
        
        most common
        
        ileum
        
        absorption site
        
        amino acid
        
        water soluble vitamins
        
        sugar
        
        glucose
        
        fructose
        
        transport process
        
        at the terminal -contain some bacteria
        
        less bacteria than large intestine
    - - microflora abundant
      - drug decomposition here
      - colon
        
        lack villi
        
        limited drug absoption
        
        lined with mucin
        
        pH 5.5 - 7
        
        modified extended release dosage form absorbed here
      - rectum
        
        15 cm long
        
        drug absorption
        
        varied depend
        
        location
        
        duration placement in rectum
        
        rectal administration
      - non-disintegrating pellet - spend 80% of its time here
    - - fasting pH = 2 - 6
      - release
        
        gastrin
        
        histamine
        
        H+ = more acidic
        pH 1 - 2
      - stimulated by
        
        gastric distension -enlargement of stomach
        
        peptides
    - - saliva
      - 1500 ml/day
      - ptyalin - digest starches
    - - esophageal shpincter
      - end of the esophagus
      - prevents acid reflux from stomach
    - - intersubject variability
        
        stomach
        
        small pellets and large pellets take same time when fasted
        
        large pellet takes longer in stomach with heavy breakfast
        
        large pellets take longer with light breakfast
        
        small intestine
        
        same for
        
        fasted
        
        light breakfast
        
        heavy breakfast
      - intrasubject variability
        
        colon
        
        normal
        
        6 hour- several days
        
        average 12-30 hours
        
        diarhea
        
        few hours
        
        constipation
        
        5 days or more
        
        more transit time comparing to stomach and small intestines
        
        STOMACH & small intestine
  - - - released after 4-5 hours
      - fasting - absorbed in colon
      - food - longer to reach colon
- - - - anticholinergic
      - narcotic analgesics
      - temifentanil
    - - metoclopramide
      - make stomach absorb faster than eliminating
- - - - independent
      - of retention of product in stomach
  - - - stomach - coated with material resistant to acidic environment
      - intestinal fluids - break down
    - - fasted
        
        intact tablet
        
        pass thru stomach
        
        into intestine
        
        20min - several hours
      - fed
        
        12h
    - - EC small granules
      - reliable rate of delivery in intestines
      - less dependent on
        
        single event
        
        food intake
        
        "house-keeping" wave
  - - - drug release
        
        to small intestine epithelium
      - drug absorbed
        
        by carrier-mediated process
        
        poorly absorbed in large intestine
    - - sparingly soluble
      - retain in stomach - :arrow_up: bile secretion
      - prolong dissolution in upper GI tract - :arrow_up: overall oral absorption
    - - stomach - 0.5
      - jejenum - 1.25 h
      - ileum - 1.5h
      - ileocecal junction - 1.25
      - colon - 20 h
  - - - PPI
        
        omeprazole
        
        lansoprazole
        
        pantoprazole
      - antibiotic
        
        azithromycin
      - antiviral
        
        didanosine
    - - aspirin
      - sulfasalazine -ulcerative colitis
      - bisacodyl - laxative
    - - in gastric milieu
      - undergo greater decomposition when taken with food/fats
      - exposed to low pH for longer periods of time
    - - fasted state- faster rate of absorption
      - results more complete bioavailability
      - take drug with large volume of water
        
        stronger concentration gradient
        
        better dissolution
        
        more gravity
        
        faster to site of absorption
- - - - absorb into systemic circulation from GI requires to move thru membrane
      - some drugs undergo both
        
        transcellular absorption
        
        paracellular absorption
  - - - NET OF PENETRATION
        
        permeability
        
        nature function of the membrane
        
        surface area
        
        increase in surface area in small intestine to a cylinder
        
        villi - 30
        
        cylinder - 1 relative surface area
        
        microvilli - 600
        
        folds of kerckring - 3
        large flap in lumen of intestines
        
        concentration difference across the membrane
      - drug difference that affect permeability
        
        molecular size
        
        lipophilicity
        
        lomustine - very lipophilic, cross the blood brain barrier easily
        
        apipodophyllotoxin - low lipophilicity, not likely to cross membrane
        
        exception
        
        vinblastine
        
        vincristine
        
        very lipophilic but other factors keep them from penetrating blood brain barrier
        
        charge
        
        exception - capillary membrane
        
        transport molecules
        
        ionize
        
        depending on ambient pH
        
        is greatly affected by the pH
        
        weak acids
        
        better absorbed under acidic condition
        
        primarily unionzied
        
        SHOULD BE ADDED AFTER LISTENING TO SLIDE 60
        
        bases
        
        better absorbed at higher pH
        
        bases are less ionized
        
        shape
      - PERFUSION
        
        more in small intestines
        
        resulted in drug carried away from the absorption site
        
        because of greater blood flow per volume tissue
        
        in rat
        
        perfusion-rate limit (rate of passage)
        
        because permeation in jejunum is so rapid
        
        blood flow is the determination
        
        for ribitol
        
        blood flow not affect transport rate
        
        permeability-rate limited
- - - - transported by
        
        enzyme
        
        transporter
    - - renal secretion
        
        acid
        
        base
      - biliary secretion
        
        acid
        
        base
      - central nervous system
        
        secretion of certain acids
      - intestinal absorption
        
        amino-beta-lactam antibiotics
        
        angiotensin-converting enzyme inhibitors
        
        via dipeptide transport system
    - - influx transporter
      - efflux transporter
        MDR1
      - consequences of efflux transporter
        
        transport all the drugs out of the blood/ active site
  - - - exclude / remove materials
      - sequester vital substances
      - selectively retain vital substances
      - maintain cellular environment
      - substrates
        
        endogenous compounds
        
        close analogs
      - the concept comes from
        
        observation of limited rate of transport
        
        at increase substrate concentrations
  - - - cannot transverse
      - cell membrane
  - - - no net expenditure of energy
      - at equilibrium, concentration remains constant
        
        in cell
        
        surrounding the cells
      - high plasma glucose concentration
        
        rate of transport into erythrocyte
        
        reaches a limiting value
        
        transport maximum
      - glucose transport
        
        carrier-mediated
        
        specific
        
        inhibited by other substances
      - drug under go this
        
        cytarabine
        
        gemcitabine
      - depend on concentration gradient
    - - movement of glucose into erythrocytes
      - intestinal absorption of
        
        nucleosides
        
        nucleobases
  - - - inner lipoidal matrix
      - two surfaces covered by
        
        continuous protein
        
        lattice work of protein
      - hydrophobic portion of
        
        oriented towards the center
        
        lipid molecules
      - hydrophilic regions
        
        face surrounding aqueous environment
      - aqueous-filled channels
        
        narrow
        
        exist between some cells
        
        capillary membranes
        
        intestinal epithelia
    - - movement across series of
        
        membranes
        
        spaces
      - these series serve as functional macroscopic membrane
      - interposing membrane - impede drug transportation
  - - - passive
        
        depends on concentration gradient
      - facilitated transcellular
- - - - expected
        
        unccharged lipophilic drugs to rapidly absorbed in the GI
        
        hydrophilic drugs not absorbed as well in GI
      - expanded theory
        
        paracellular absorption - small hydrophilic rapid absorption
        
        discoveries
        
        tumor cells resistant to anticancer drugs
        because of efflux transporters
        
        gut wall metabolism
        first-pass effect
    - - apical side of many cells
      - GI tracts
        
        tips of villi
        
        jejunum
        
        enterocytes
      - central nervous system
      - liver
      - kidney
      - pancreas
      - adrenal gland
    - - immunosuppressive agent
      - reduced systemic bioavailability
      - because of gut wall metabolism
    - - antiviral
      - highly selective inhibitor of HIV protease
      - absolute bioavailability of 4%
      - co-administration
        
        ratonavir
        
        potent inhibitor of
        
        cyp3a
        
        P gp
        
        saquinavir
        
        therapeutic effect
        
        increase absorption of saquinavir
        
        :arrow_down: need to administer with heavy meal
        
        reduces frequency dosing tid:arrow_right: bid
        
        :arrown_down: daily dose 3600 -> 2000 mg
        
        decrease inter-subject variability
        
        high metabolism ppl :arrow_right: slow metabolism
        
        slow metabolism pp :arrow_right: slightly slower metabolism
  - - - not inert barriers
      - specialized function
      - polar compounds
        
        low lipid solubility
        
        penetrate membranes faster
        
        passive diffusion
    - - low lipid solubility
      - penetrate faster thru passive defusion
      - thru an inert lipoidal barrier
  - - - gut wall metabolism
      - back transport into lumen of intestine
      - can be recycled many times
      - low oral bioavailability is because
        
        efficient back transport of drug
        
        metabolism of CYP3A - repeated exposure to the enzyme
      - increase bioavailability by inhibiting
        
        back transport
        
        metabolizing enzymes
      - CYP3A can affect different drugs given at the same time
      - grapefruit
        
        inhibits CYP3A activity
        
        absorb more drugs
        
        adverse effect
      - transporter variation between people
        
        similar quantity
        
        different quality