Transcript MD-2-Bioavailability and Pharmacodynamic

Standardization, Bioavailability,
Pharmacodynamics, Pharmacokinetics,
etc.
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Plant material
Directly
Fresh
Extract
Dried
Powdered
Ingested
Topically
EtOH
Coarse powder
Standard
powder
concd.
Comminuted
jar
box
tisan
Teinture
Extraitfluide
Herbal tea
Drops
Herbal tea
Solution
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Standardized
dried extract
ointment
Syrup
capsule
tablet
H2O
H2O/EtOH
Aceton
tablet/
capsule
instant tea
injection
2
Standardization

Only “Standardized
vegetable drugs
or extracts” can find a place in Current
drug concept
I.
II.
Analytical Standardization
Clinical Standardization
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
1. Bioequivalence
 Biological effects of two plant extracts/formulations
are clinically found identical in pharmacologic and
biochemical analysis.
 Bioequivalence is necessary for similar
pharmacodynamic, pharmacokinetic and
bioavailability features of a medicine.
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The results from pharmacological and clinical trials
with one HMP could thus not automatically be
transferred to another preparation.

2. Phyto-equivalence:
 Analytical composition of two plant extracts are
chemically found identical in quantitative analysis.
 The use of different conditions, extraction solvents,
and purification steps resulted in extracts of different
quality.
 Phyto-equivalence is not a satisfactory proof for
biological/pharmacological effects; needs further
bioequivalence studies in small groups.
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Standardization:
A. If the Active component(s) is
known

Active component(s) is used for analytical
standardization
 Ginkgo biloba (Ginkgo) prep.
Compound for standardization: Ginkgolides or
flavonoids
(Tebokan®, Ginkgobil®, etc.)
 Senna leaves
Compound for standardization: Sennoside B
(Pursenid®, Roha®, Bekunis®, Senekod®, XM® etc.)
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Standardization:
B.
Unknown active constituents

a. “Marker component(s)”
Standardization may be achived by using any
plant constituent(s), even the role on the
claimed activity is unknown:
 Valeriana (Valerian; kediotu) root
valerianic acid (a sesquiterpene)
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C. “chromato-fingerprinting”

Chromatographic identity” of a
 ”
certain extract is determined by using:




Thin-layer chromatography (TLC)
Gas-liquid chromatography (GLC); for volatile compounds
High performance liquid chromatography (HPLC)
High performance thin-layer chromatography (HP-TLC)
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TLC or HP-TLC fingerprinting of Hawthorn

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Saw Palmetto (Serenoa repens)
Benign Prostate Hyperplasia (BPH)
treatment

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–Gas-liquid chromatography
fingerprinting of Saw Palmetto
High performance liquid chromatography fingerprinting
of EGb761 (Ginkgo biloba)

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Bioavailability
Pharmacokinetic
Pharmacodynamic
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Evidence of efficiency for HMPs

Number of Clinical evidences are few!
The evidence has been mainly from
 Ethnomedical knowledge,
 Anecdotal or hearsay.
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Optimizing Efficacy

 Phytochemicals may interfere with meals;
 Polyphenolics should be taken away from meals because of
their interaction with proteins.
 Components relying on gastric acid hydrolysis should be
taken with meals,
 Components damaged by gastric acid should be taken away
from meals.
 Some foods may interfere the metabolism of drugs; e.g.
Grapefruit juice, etc.
 The frequency of dosage should be adjusted based
on the bioavailability and metabolism data of the
drug.
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Bioavailability of HMPs

 HMPs are not directly introduced into the
bloodstream by parenteral injection &
 Oral or topical routes of administration are
preferred for HMPs;
 subjected to a series of metabolic processing before
absorption from GI system.
 Conventional drugs are designed to have good
bioavailability on oral application,
 HMPs may exhibit unusual and poor
bioavailability,
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Some components in the blend may potentiate the
Bioavailability of the drug

Protecting the active components from
structural transformation to inactive
metabolite,
Increasing the absorption of the active
compound(s) from digestive system,
Sharing the activity: “Synergy”
Reducing the unwanted effects
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1.“Synergistic interaction” of several components in a
herbal extract:

 In plant material/extract the biological effect may be
achieved by synergistic interactions;
 Separation of the active ingredients may lead to
reduced efficiency or lost in activity.
e.g. Ginkgo, Kava
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Ginkgo biloba

 A mixture of pure Ginkgolides A, B and C at a dose of
100-240 mg can generate a PAF-antagonizing effect in
humans.
 Same efficiency may be provided with a dose of 120 mg of
a “Standardized Ginkgo extract” containing only 6-7 mg
of ginkgolides together with bilobalide and flavonol
glycosides.
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Ginger, Zingiber officinalis,
as antiulcer

Active fraction contain;“
a-zingiberen,
b-sesquiphellandrene, bisabolene
and curcumene,
Constitutes only a small portion of
the active fraction;
The effect was x6 higher than
calculated from a summation of the
individual
ingredients.
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“Synergistic interaction ”: Combination of
herbal extracts may potentiate the efficiency

 Product: Ginseng/Ginkgo combination
 Study: A double-blind crossover trial in 20 young
healthy volunteers,
 Effect: Improving cognitive function
 Result: More effective than either alone
Scholey AB, Kennedy DO, 2001: Acute, dose-dependent cognitive effects of Panax
ginseng and Ginkgo biloba and their combination in healthy young volunteers:
differential interactions with cognitivedemand.
Human Pyschopharmacology.
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2.Some constituents may regulate absorption or
metabolism rate

Removal of some pharmacologically inactive
constituents, but involving in pharmacokinetic
and/or pharmacodynamic interactions may
lead to
LOST IN ACTIVITY
due to diminishing rate of absorption of the
active constituents.
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Higher
Bioavailability
is observed for
Ascorbic acid
in citrus fruits
(orange,lemon, mandarin,
etc.) then in formulations
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Postmenaposal Syndrome
estrogenic activity 
isoflavon glycosides
“daidzin”’
In extract > pure daidzin
Higher plasma
concentration
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
Saponins (a type of plant constituents); improve
absorption and/or solubilization due to
higher surface activity characteristics,
St.John’s wort (Hypericum) an antidepresant
HMP; procyanidins/flavonoids increase the
absorption of active constituents
(hypericin/hyperforin):
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Lemongrass volatile oil (Cymbopogon sp.)

Antibacterial components;
geranial and neral
Another component myrsene’ possesses no
antibacterial activity, but increase the
effect of other two components
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3. Some constituents may help protection of the
unstable active constituents from chemical
degradation to inactive metabolites:
Antioxidants, may protect the active ingredients
from oxidative decomposition:
 Pure Hyperforin (active principle of St.John’s wort)
easily decomposed by oxidation when isolated,
 Antioxidant “procyanidins” in the crude extract
protect the compound from oxidative decomposition.
 Therefore “St.John’s wort” crude extract is used in
HMP formulations.
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4. “Preactivation” may be
required to activate the
constituent before
administration:

 Some plant ingredients are in “PRODRUG”
form and they should be converted into ACTIVE
FORMS before administration.
In “Garlic”
-“Alliin” is an inactive precursor or “prodrug”
- Enzymatically (allinase) converted to active
metabolite “allicin” when the cells are crushed.
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5. Activity may be lost
during processing or
storage

Activity may be lost due to heat or sunshine:
 Volatile components may be lost (volatile oils).
Volatile constituents of Mint leaves
evaporated if dried under sunshine or in
an oven.
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5. Activity may be lost
during processing or
storage

Activity may have lost critically due to
structural decomposition:
 Heat decompose proteic components/enzymes
/sulfur-containing:
 In Broccoli, heat decomposed the enzyme
(myrosinase) needs to convert glucoraphanine
into active metabolite sulfurophane.
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5. Activity may be lost during processing or
storage

Activity may be lost due to moisture:
 Moisture may initiate the enzymatic reactions to
cause inactivation of the active molecule.
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6. Buffer constituents may prevent the
undesirable effects

 Removal of “Buffer constituents” may increase the risk
of HMP:
Advers effects/or
Contrindications/or
Toxicity.
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
Chemical structure of the ingredients may be
subjected to change
By saliva
By gastric juice (pepsin/gastric acid)
By bile acids
By pancreatic juice
By intestinal flora
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
 Changes induced by hepatic drug-metabolizing
enzymes
 Binding of active ingredients to their receptors and to
plasma albumin
 Changes in the chemical structure and concentration of
active ingredients in the blood and excretion into the
urine, bile and feces.
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On oral administration:
I. After ingestion components

 Pass through the GI tract
 Metabolized by the enzymatic action of intestinal
bacterial flora
 Absorbed into the blood.
II. Some components are directly absorbed
 Detoxified in the liver
 Excreted in the bile to interact with intestinal flora for
biotransformation,
 Then reabsorbed
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“Herbal Pharmacokinetics“
extraordinarily complex to study

Plants have complex chemical composition;
 Potential interactions between the plant constituents:
synergistic, antagonistic,
 Mixture of different compounds in the HMP with
different bioavailability,
 Active components are often not known or activity is
shared by several components, therefore the
component(s) in the extract can not be targeted,
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“Herbal Pharmacokinetics“
extraordinarily complex to study

Prodrug;
Natural compounds are often metabolized in
the digestive tract;
Thus pharmacokinetic characteristics are not
predictable,
Large molecules are often involved, which
might be expected to have poor and
unpredictable bioavailability.
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Key issues pertaining the
bioavailability

 Solubility characteristics of the components:
 Liposolubility of the molecule increase the
bioavailability,
 H2O-soluble molecules can be expected to have poor
bioavailability,
 Ionization of the molecule usualy means poor
bioavailability,
 A molecule possessing both H2O and fat soluble
parts will exhibit very good bioavailability;
 Dissolve in digestive juices and then cross lipid
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membranes.
Effect of liposolubility on bioavailability
Cardiac glycoside
Partition between H2O
and octanol
Bioavailability
(%)
g-Strophanthin
0.01
6.6
Convallatoxin
0.33
13.6
Digoxin
18.2
26.4
Digitoxin
70
74.9
Oleandrin
338
86.0
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Key issues pertaining the bioavailability

A small portion of relatively large molecules,
Size of the molecule;
i.e. Saponins, tannins, polysaccharides,
proteins, will be absorbed.
Even very large molecules may still have
some bioavailability (<1%); pinocytosis.
Specific factors for crossing the gut wall;
active transportation,
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Key issues pertaining the bioavailability
Factors involved within the gut;

Interaction with food,
Interaction with the pharmacotherapy,
Stability in the gut,
Gastric emptying rate,
Individual factors of the patient:
Influence of personal pathological factors.
Genetical factors: absence of particular
drug metabolizing enzymes,
Age and gender.
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Key issues pertaining the bioavailability
 The type of pharmaceutical preparation:
 Infusions and decoctions extract H2O-soluble
components,
 Many of these polar components will have poor
bioavailability,
 They are inferior preparations for extraction and
delivery of herbal constituents.
 HMPs rely heavily on aqueous preparations;
 Infusion of VO-containing plant;
 VO will be collected on the surface of the hot H2O.
 Addition of saponin-containing herbs to the mixture
will increase the solubility of H2O-insoluble
compounds, which may then have better
bioavailability.
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
Key issues pertaining the bioavailability

 Metabolism in the gut and first-pass metabolism by
the liver,
 H2O-soluble components may subjected to structural
changes in the GI tract;
Glycosides are converted to aglycones in the
caecum and large bowel, will render them more
liposoluble and increase bioavailability.
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GLYCOSIDES
and Gastric modification

 A number of plant glycosides are modified
 By the action of gastric acid or
 By the alkaline conditions of duodenum.
 By the intestinal flora of bowel.
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Pharmacodynamics of glycosides
 Glycosides:

 H2O- soluble
 Poorly absorbed in the intestines
 Low bioavailability; it does not mean low activity????
 Metabolic transformation of glycosides
 In the Stomach:
 If resistant to gastric acid and digestive enzymes, pass
unabsorbed through the upper intestinal tract.
 In the intestines:
 Retained in the lower GI tract
 Enzymatic transformation: Mostly hydrolyzed to the
corresponding aglycones by intestinal anaerob bacterial
glycosidases
 Then absorbed slowly and continuously to exhibit
pharmacological activities.
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GLYCOSIDES:
Flavonoids

 Present in many phytomedicines and foods
 They may have a role to play in increasing the biological
activity of other compounds by synergistic or other
mechanisms:
 Antimalarial compound Artemisinin
(sesquiterpenoid), from Artemisia annua, activity
enhanced by the presence of the flavonoids
“armetin” and “casticin”.
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Flavonoids

 Only <20% of the administered glycoside will generally
be absorbed as the intact aglycone.
 Levels of a flavonoid aglycone in the blood stream will
vary depending on;
 Flavonoid form; aglycone or glycoside,
 Flavonoid glycosides are prodrug form
 The nature of the individual bowel flora;
 Partialy dependent on the individual diet.
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Oral doses of flavonoid aglycones are less bioavailable
than their glycosides,
They are more susceptible to “C-ring fission” by
the bowel flora,

C-FISSION
OH
OH
B
B
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O
A
C
HO
OH
O
Flavonoid
O
m-hydroxyphenylpropionic acid
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Pharmacokinetics of flavonoid glycosides
Too large and polar to be
absorbed
FLAVONOID-O-GLUCOSIDE

Hydrolysis of -linkage
by bacterial enzymes
in bowel
FLAVONOID AGLYCONE
can be absorbed
ring fission by bacterial
enzymes
Absorption into the bloodstream
Smaller ring fission products
readily absorbed
Complete breakdown to CO2
Absorption into the bloodstream
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Flavonoid ring metabolites after
fission
 Quercetin, rutin:

 3,4-dihydroxyphenylacetic acid
 3-methoxy-4-hydroxyphenylacetic acid,
 m-hydroxyphenylacetic acid,
 Hesperidin, diosmin, eriodictyol:
 m-hydroxyphenylpropionic acid,
 m-coumaric acid (rat)
 3-hydroxy-4-methoxyphenylhydracrylic acid (human),
 (+)-Catechin:




D-hydroxyphenyl-g-valerolactones
m-hydroxyphenylpropionic acid
m-hydroxybenzoic acid
m-hydroxyhippuric acid
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In particular cases different pharmakokinetic
ways may be observed
Baicalin

Flavonoid from Scutellaria roots
Antiallergic, stimulate bile secretion
Baicalin is not directly absorbed
Circulating conc. of “baicalin” was found higher than
“baicalein glucuronide”
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GlcUA
O
O
HO
HO

O
OH
O
HO
OH
Baicalin (BG)
Baicalein (B)
Intestine
BG
Intestinal flora
 -glucuronidase
O
Blood circulation
Intestinal cell
B
B
BG
BG
UDPG-glucuronyl
transferase
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GLYCOSIDES:
Isoflavones

Affinity to oestrogen receptors;
 Soy beans: Soja hispida
 daidzin (daidzein), genistin (genistein)
 Red clover: Trifolium pratense
 formononetin, biochanin A
 formononetin is converted to daidzein
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Isoflavones are converted by the bowel
flora to “EQUOL” which possesses stronger
oestrogenic activity than its precursor.

RO
O
RO
O
bowel flora
R1
O
R1
OH
OH
EQUOL
R=R1=H
Daidzein
R=Glu
R=H
R1=H
R1=OH
Daidzin
Genistein
R=Glu
R1=OH
Genistin
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
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
Lactococcus garvieae
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 Soy isoflavones are degradated up to 85% in the intestines.
 Differences in the fecal flora account for the differing metabolism of soy
isoflavones.

 Faecal flora could completely degradate isoflavonoid (genistein and
daidzein).
 Differences in faecal excretion of isoflavones profoundly altered
isoflavone bioavailability:
 Higher faecal excretion is correlated with higher bioavailability.
Such subjects may have fewer bacteria which degrade isoflavones,
leaving more intact for absorption.
 Bioavailability varied from 13 -35% depending on the individual
gut microflora.
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
 Soy protein: contains isoflavone glycosides;
 increase follicular phase length in women,
 Miso: contains isoflavone aglycones:
 Not affect.
 Suggests that the glycosidic group delays the
degradation of isoflavones, resulting in higher
bioavailability of their aglycones or equol.
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Urinary excretion rates of daidzein and 2 metabolites after soya administration
over 3 days
Mean excretion (mmol)/3 days
Metabolite Low equol producers
< 8 mmol equol (n=8)
High equol producers
< 25 mmol equol (n=4)
Daidzein 23.05 (12.43)
14.95 (6.69)
Equol
1.53 (2.60)
64.89 (59.23)
O-Dma
21.72 (17.93)
6.97 (6.47)
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GLYCOSIDES:
Phenolic glycosides
Salicin from Salix ssp. Barks

CH 2OH
O-Glu
Salicin
COOH
CH 2OH
OH
OH
Salicyl alcohol
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Salicylic acid
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GUT
Salicin
Salicortin
Tremulin
Tremulacin
stomach
or small intestine
Salicin
small intestine
intestinal bacteria
(colon or distal column)
Salicyl alcohol
(Saligenin)
URINE
(Over 24 h)
BODY FLUIDS
large intestine

Salicin
excretion
Salicin
enzymes in
blood and tissue ?
Salicyl alcohol
excretion (4%)
Salicyl alcohol
oxidation in blood,
tissue and liver
excretion (12%)
Salicylic acid
Salicylic acid
Hepatic biotransformation
Salicylic acid
conjugates
Gentisic acid
excretion (65%)
Salicylic acid
conjugates
excretion (5%)
Gentisic acid
Pharmacokinetics of salicin
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Relative bioavailability of salicin and salicylic acid

salicin has a greater half-life
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 Devil’s claw: Harpagophytum procumbens,
 Harpagoside; Oral anti-inflammatory activity,
 In stomach; gastric acid convert to “harpagogenin”,
possess no anti-inflammatory activity,
 Suggested to
 Use enteric coated tablets or
 Administer between meals to optimize the bioavailability.

GLYCOSIDES:
Iridoids
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GLYCOSIDES
:Anthraquinone Glycosides

Laxative effect
Orally: in equivalent doses
 only glycosides active,
 takes 6-8 h to exert laxative effect,
 effective dose often varied from person to person,
 aglycones not active; broken down or absorbed before
reaches the colon
Injection: in equivalent doses
 aglycone was more active,
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Sinameki (Senna) leaves
 Active ingredients:
antraquinones;
 Sennoside A and C showed similar
degree of laxative effect in mice,
 In leaves they are in the ratio of 7:3
which shows 2x higher activity
Formulations (Pursenid®, Senekot®, Bekunis®, Roha®) are
prepared using the standardized extract
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
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GLYCOSIDES: Diterpenoids
Salvia divinorum
 Hallucinogenic: fresh leaves are chewed,
 Salvinorin A (1) [active] is converted to salvinorin B
(2) [inactive] by gastric acid.
 Chewing; provide absorption from oral mucosa,
without decomposition.
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GLYCOSIDES:
Triterpenes glycosides
Saponins

 Saponins are good “prodrugs”
 Small intestines:
 Due to water solubility not absorbed,
 Pass to large intestines;
 Converted by the gut flora to the sapogenins,
 Sapogenins are lipophylic and absorbed to some
extent.
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Saponin type compounds increase the gastro-
intestinal absorption rate of other components in the
multi-component drugs.

Saponin-containing plants i.e., licorice (meyan kökü), were
used in Oriental Medicines in order to
 increase absorption of components,
 Co-ordinate the effect of components in formulations, like a
“chorus-conductor” as well as for detoxification.
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Licorice:
Glycyrrhizin (triterpenoid saponin)
Orally administered

 Hepatoprotective
 Antiviral against HIV-1
Pharmacokinetic studies:
 Glycyrrhizin is converted to Glycrrhetinic acid
(aglycone) in the human intestinal flora,
 Glycrrhetinic acid is found as the predominant form
in the blood,
 Only “Glycrrhetinic acid-glucuronide metabolite”
possesses antiviral and antihepatotoxic activity.
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COOH

Glycyrrhizin
COOH
O
O
COOH O
O
OH
HO
COOH
O O
HO
Human feces
Eubacterium sp.
(glycyrrhizin -glucuronidase)
OH
HO
Glycyrrhetic acid
OH
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:
GLYCOSIDES Cardioactive glycosides

 Digitoxin; absorbed quantitatively,
 Oral and i.v. doses are same.
 Digoxin is excreted largely unchanged in the urine.
 Ouabain (from Strophanthus sp.)
 has poor and erratic oral absorption,
 only be given by injection.
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Tannins/Procyanidins

Principally low bioavailability
 Large molecular weight
 High affinity to bind with proteins
 Poor lipid solubility
 Poor bioavailability of intact tannins is important
to avoid from toxic effects;
 Hepatotoxicity: Hydrolysable tannins absorbed into
the bloodstream cause,
 Cancerogenicity (on sc.)
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
Breakdown products of tannins take place
 in the large bowel by bowel flora,
 in the small bowel for hydrolysable tannins,
Metabolites show potent antioxidant activity.
“Pycnogenol”:
 Oligomeric proanthocyanidin (OPC) [condensed tannin];
 antioxidant in pine bark.
Cross the blood-brain barrier (?)
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Lifecycle of tannin through the gut

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
pH 7-8
caecum microflora
CONDENSED TANNINS
HYDROLYSABLE TANNINS
(TANNIC ACID)
pH 7-8
caecum microflora
ELLAGIC ACID
Antioxidant
anticancer
GALLIC ACID
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 Polyphenol in Tea
 Green tea:

 EGCG: Epigallocatechin gallate
 EGC: Epigallocatechin
 Black tea:
 Fermentation; leads to polymerization to more complex
molecules (mw 500 to 3000);
 Theaflavins,
 Thearubigens,
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
Clinical:
 Green tea and black tea provide a significant increase in
the antioxidant activity of plasma,
 Antioxidant activity;
 Green tea > black tea
 in vitro x5;
 in vivo x2 times
 The effect is rapid, peaking at
 ~ 30 min after green tea,
 ~ 50 min after black tea consumption.
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
EGCG is stable in the upper digestive tract
 Possibly tea polyphenols undergo spontaneous
decomposition in the gut and the smaller antioxidant
molecules are then absorbed.
 However 0.2-2.0% of the orally administered EGCG
was found to be absorbed in the blood after 90 min
without any decomposition.
 40% of EGCG at 50 mg dose administered orally to
rats was excreted unchanged with the faeces.
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
Adding milk completely detroy antioxidant
effect of tea.
 Causes protein binding would inhibits
decomposition of polyphenolic constituents and
thus bioavailability.
 NB: the tannin-protein complex later may yield
metabolites in the gut and may show activity.
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Polysaccharides

 Role as immune-enhancing agents,




Echinacea
Urtica
Ginseng
Ganoderma (reishi mushroom)
 Macromolecules composed of sugar and uronic acid
moiety,
 In plants is a component of cell wall.
 H2O-solubl or swelling molecules,
 EtOH or EtOH/H2O (less than 50%) extracts generally
do not contain polysaccharides
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
Polysaccharides possess low bioavailability,
Advised to be administered in sufficient
doses for compensation of the poor
bioavailability.
Unabsorbed polysaccharides
 Pass into the large intestine,
 Broken down by bowel flora ,
 Also may have a protective role balacing bowel
flora.
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