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E. Yeşilada 1
Standardization, Bioavailability,Standardization, Bioavailability,Pharmacodynamics, Pharmacodynamics,
Pharmacokinetics, etc.Pharmacokinetics, etc.
E. Yeşilada 2
Plant material
Directly Extract
Fresh Dried
IngestedTopically
Powdered Comminuted
jarboxtisan
Herbal teaStandardpowder
Coarse powder
Herbal tea
capsuletablet
EtOH H2OH2O/EtOH
Aceton
concd.
Standardizeddried extract
TeintureExtraitfluide
tablet/capsule
instant tea
ointment
injection
Syrup
Drops
Solution
Only “Standardized vegetable
drugs or extracts” can find a place in Current drug concept
I. Analytical StandardizationII. Clinical Standardization
E. Yeşilada 3
Standardization
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.
E. Yeşilada 4
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.
E. Yeşilada 5
E. Yeşilada 6
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.)E. Yeşilada 7
Standardization: A. If the Active component(s) is
known
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)
E. Yeşilada 8
Standardization:
B. Unknown active constituents
”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)
E. Yeşilada 9
C. “chromato-fingerprinting”
10
TLC or HP-TLC fingerprinting of Hawthorn
E. Yeşilada 11
Saw Palmetto (Serenoa repens)Benign Prostate Hyperplasia (BPH)
treatment
–Gas-liquid chromatography fingerprinting of Saw Palmetto
E. Yeşilada 12
High performance liquid chromatography fingerprinting of EGb761 (Ginkgo biloba)
E. Yeşilada 13
BioavailabilityBioavailabilityPharmacokineticPharmacokinetic
PharmacodynamicPharmacodynamic
Number of Clinical evidences are few! The evidence has been mainly from
Ethnomedical knowledge, Anecdotal or hearsay.
E. Yeşilada 14
Evidence of efficiency for HMPs
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.
E. Yeşilada 15
Optimizing Efficacy
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,E. Yeşilada 16
Bioavailability of HMPs
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
E. Yeşilada 17
Some components in the blend may potentiate the Bioavailability of the drug
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
E. Yeşilada 18
1.“Synergistic interaction” of several components in a herbal extract:
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.
E. Yeşilada 19
Ginkgo biloba
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.
E. Yeşilada 20
Ginger, Zingiber officinalis,as antiulcer
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
E. Yeşilada 21
“Synergistic interaction ”: Combination of herbal extracts may potentiate the
efficiency
Scholey AB, Kennedy DO, 2001: Acute, dose-dependent cognitive effects of Panax Scholey AB, Kennedy DO, 2001: Acute, dose-dependent cognitive effects of Panax ginseng and Ginkgo biloba and their combination in healthy young volunteers: ginseng and Ginkgo biloba and their combination in healthy young volunteers: differential interactions with cognitivedemand. Human Pyschopharmacology.differential interactions with cognitivedemand. Human Pyschopharmacology.
Removal of some pharmacologically inactive constituents, but involving in pharmacokinetic and/or pharmacodynamic interactions may lead to
LOST IN ACTIVITYdue to diminishing rate of absorption of the active constituents.
E. Yeşilada 22
2.Some constituents may regulate absorption or metabolism rate
Higher
Bioavailabilityis observed for
Ascorbic acidin citrus fruits
(orange,lemon, mandarin, etc.) then in formulations
E. Yeşilada 23
E. Yeşilada 24
Postmenaposal Syndrome estrogenic activity
isoflavon glycosides “daidzin”’
In extract > pure daidzin
Higher plasma concentration
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):
E. Yeşilada 25
Antibacterial components;
geranial and neralAnother component myrsene’ possesses
no antibacterial activity, but increase the effect of other two components
E. Yeşilada 26
Lemongrass volatile oil (Cymbopogon sp.)
E. Yeşilada 27
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.
3. Some constituents may help protection of the unstable active constituents from
chemical degradation to inactive metabolites:
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.
E. Yeşilada 28
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.
E. Yeşilada 29
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.
E. Yeşilada 30
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.
E. Yeşilada 31
5. Activity may be lost during processing or storage
Removal of “Buffer constituents” may
increase the risk of HMP:
Advers effects/or Contrindications/or Toxicity.
E. Yeşilada 32
6. Buffer constituents may prevent the undesirable
effects
E. Yeşilada 33
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
E. Yeşilada 34
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.
E. Yeşilada 35
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
E. Yeşilada 36
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,
E. Yeşilada 37
“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.
E. Yeşilada 38
“Herbal Pharmacokinetics“ extraordinarily complex to study
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
membranes.E. Yeşilada 39
Key issues pertaining the bioavailability
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
E. Yeşilada 40
Size of the molecule; A small portion of relatively large
molecules, 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,
E. Yeşilada 41
Key issues pertaining the bioavailabilityKey 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. E. Yeşilada 42
Key issues pertaining the bioavailabilityKey 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.E. Yeşilada 43
Key issues pertaining the bioavailabilityKey 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.
E. Yeşilada 44
Key issues pertaining the bioavailabilityKey issues pertaining the bioavailability
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.
E. Yeşilada 45
GLYCOSIDES and Gastric modification
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.
E. Yeşilada 46
Pharmacodynamics of glycosides
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”.
E. Yeşilada 47
GLYCOSIDES: 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.
E. Yeşilada 48
Flavonoids
O
OH O
OH
A C
B
Flavonoid
HO
O
OH
B
m-hydroxyphenylpropionic acid
C-FISSION
E.
Yeşi
lada
49
Oral doses of flavonoid aglycones are less bioavailable than their glycosides,
They are more susceptible to “C-ring fission” by the bowel flora,
FLAVONOID-O-GLUCOSIDE
FLAVONOID AGLYCONE
Too large and polar to beabsorbed
Hydrolysis of -linkageby bacterial enzymes
in bowel
can be absorbed
ring fission by bacterialenzymes
Absorption into the bloodstream Smaller ring fission products readily absorbed
Complete breakdown to CO2
Absorption into the bloodstream
E. Yeşilada
50
Pharmacokinetics of flavonoid glycosidesPharmacokinetics of flavonoid glycosides
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: -hydroxyphenyl--valerolactones m-hydroxyphenylpropionic acid m-hydroxybenzoic acid m-hydroxyhippuric acid
E. Yeşilada 51
Flavonoid ring metabolites after fission
Baicalin
Flavonoid from Scutellaria roots Antiallergic, stimulate bile secretion Baicalin is not directly absorbed Circulating conc. of “baicalin” was
found higher than “baicalein glucuronide”
E. Yeşilada 52
In particular cases different pharmakokinetic ways may be observed
O
OOH
HO
OO
OOH
HO
HOGlcUA
Baicalein (B)Baicalin (BG)
Intestine Intestinal cell Blood circulation
BG B B BG BG
Intestinal flora -glucuronidase UDPG-glucuronyl
transferase
E. Yeşilada 53
Affinity to oestrogen
receptors; Soy beans: Soja hispida
daidzin (daidzein), genistin (genistein)
Red clover: Trifolium pratense formononetin, biochanin A formononetin is converted to
daidzein
E. Yeşilada 54
GLYCOSIDES: Isoflavones
O
O
RO
OHR1
R=R1=H Daidzein
R=Glu R1=H DaidzinR=H R1=OH Genistein
R=Glu R1=OH Genistin
ORO
OHR1
EQUOL
bowel flora
E. Yeşilada 55
Isoflavones are converted by the bowel flora to “EQUOL” which possesses stronger oestrogenic activity than its precursor.
56Erdem Yeşilada
57
Lactococcus garvieae
Erdem Yeşilada
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.
E. Yeşilada 58
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.
E. Yeşilada 59
Urinary excretion rates of daidzein and 2 metabolites after soya administration over 3 days
Mean excretion (mol)/3 days
Metabolite
Low equol producers< 8 mol equol (n=8)
High equol producers< 25 mol 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)
E. Yeşilada 60
CH2OH
O-Glu
Salicin
CH2OH
OH
COOH
OH
Salicyl alcohol Salicylic acid
E. Yeşilada 61
GLYCOSIDES: Phenolic glycosides Salicin from Salix ssp. Barks
BODY FLUIDSGUT
SalicinSalicortinTremulin
Tremulacin
stomachor small intestine
Salicin
intestinal bacteria(colon or distal column)
Salicyl alcohol(Saligenin)
Salicin
Salicyl alcohol
Salicinsmall intestine excretion
large intestine excretion (4%)Salicyl alcohol
enzymes inblood and tissue ?
oxidation in blood,tissue and liver
excretion (12%) Salicylic acid
Hepatic biotransformation
Salicylic acidconjugates
Salicylic acidconjugates
excretion (65%)
Gentisic acidexcretion (5%)
Gentisic acid
URINE(Over 24 h)
Salicylic acid
E. Yeşilada 62Pharmacokinetics of salicinPharmacokinetics of salicin
E. Yeşilada 63
Relative bioavailability of salicin and salicylic acid
salicin has a greater half-life
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.
E. Yeşilada 64
GLYCOSIDES: GLYCOSIDES:
IridoidsIridoids
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,
E. Yeşilada 65
GLYCOSIDES:Anthraquinone Glycosides
E. Yeşilada 66
Sinameki (Senna) leaves Active ingredients: Active ingredients:
antraquinonesantraquinones; ; Sennoside ASennoside A andand CC showed showed similar degree of laxative similar degree of laxative effect in mice,effect in mice, In leaves they are in the In leaves they are in the
ratio of ratio of 7:37:3 which shows which shows 2x2x higher activityhigher activityFormulations (Formulations (Pursenid®, Senekot®, Pursenid®, Senekot®,
Bekunis®, Roha®Bekunis®, Roha®) are prepared using the ) are prepared using the standardized extractstandardized extract
E. Yeşilada 67
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.
E. Yeşilada 68
GLYCOSIDESGLYCOSIDES: : DiterpenoidsDiterpenoids
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.
E. Yeşilada 69
SaponinsGLYCOSIDES: GLYCOSIDES: Triterpenes glycosidesTriterpenes glycosides
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.
E. Yeşilada 70
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.
E. Yeşilada 71
Licorice: Glycyrrhizin (triterpenoid
saponin)
O
O
COOH
O
O O
OH
HO
COOH
COOH
HOHO
O
COOH
OH
OH
Glycyrrhizin
Glycyrrhetic acid
Human feces
Eubacterium sp.(glycyrrhizin -glucuronidase)
E. Yeşilada 72
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.
E. Yeşilada 73
GLYCOSIDES: Cardioactive glycosides
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.)
E. Yeşilada 74
Tannins/Procyanidins
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 (?)E. Yeşilada 75
E. Yeşilada 76
Lifecycle of tannin through the gut
CONDENSED TANNINS ELLAGIC ACID
pH 7-8caecum microflora
HYDROLYSABLE TANNINS(TANNIC ACID)
GALLIC ACID
pH 7-8caecum microflora
Antioxidantanticancer
E. Yeşilada 77
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,
E. Yeşilada 78
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.
E. Yeşilada 79
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.
E. Yeşilada 80
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.
E. Yeşilada 81
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 polysaccharidesE. Yeşilada 82
Polysaccharides
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. E. Yeşilada 83