Bio Rans Formation

BIOTRANSFORMATION
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

Department of Pharmaceutics KLE Universitys College of Pharmacy BELGAUM 590010, Karnataka, India Cell No: 0091 9742431000 E-mail: bknanjwade@yahoo.co.in
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Contents:Introduction Phase I reaction Phase II reaction Factors affecting Biotransformation Reference

Introduction:
Important terms: Detoxication (detoxification) Prodrugs
Active Metabolite
Reactive Metabolite Metabolism
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Xenobiotics
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Definition:
Biotransformation of drug is defined as the conversion from one chemical form to another. the term is used synonymously with metabolism.
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Biotransformation
Ex: Active Drug Salicylic Acid
leads to:
Pharmacologic Inactivation of Drug

Inactive Drug Salicyluric Acid
Active Metabolite From An Inactive Drug

Ex. Inactive(Prodrug) Aspirin Active Salicylic Acid
No Change in Pharmacologic Activity

Ex.
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Active Codeine
Active Drug Morphine

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Drug metabolizing organs

Liver is the heart of metabolism Because of its relative richness of enzymes in large amount. Schematic chart of metabolizing organ (decreasing order)
Liver > lungs > Kidney > Intestine > Placenta > Skin > Brain > Testes > Muscle > Spleen
Drug Metabolizing Enzymes

Microsomal
Non Microsomal
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Microsomal Enzymes
Found predominately in the smooth Endoplasmic Reticulum of liver Other areas:
Kidney Lungs Intestinal mucosa
Non-microsomal enzymes
Found in the cytoplasm and mitochondria of hepatic cells Other tissues including plasma
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Microsomal Enzymes
Non-synthetic/ Phase I reactions
Most oxidation and reduction Some hydrolysis
Non-synthetic/ Phase I reactions Most hydrolysis Some oxidation and reduction Synthetic/ Phase II reactions ALL except Glucuronide conjugation
Synthetic/ Phase II reactions
ONLY Glucuronide conjugation
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Microsomal Enzymes
Inducible
Drugs, diet, etc.
Not inducible
Why Biotransformation?
Most drugs are excreted by the kidneys. For renal excretion drugs should: have small molecular mass be polar in nature not be fully ionised at body pH Most drugs are complex and do not have these properties and thus have to be broken down to simpler products. Drugs are lipophilic in nature.
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Strongly bound to plasma proteins. This property also stops them from getting eliminated. They have to be converted to simpler hydrophilic compounds so that they are eliminated and their action is terminated.
When and How?

Biotransformation occur between absorption and elimination from kidneys. Drugs administered orally can biotransform in the intestinal wall.
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Metabolic reaction:
Phase I reaction Phase II reaction
Oxidation
Conjugation
Reduction
Hydrolysis
Phase I:
A polar functional group is either introduced or unmasked if already present on the otherwise lipid soluble Substrate, E.g. OH, -COOH, -NH2 and SH. Thus, phase I reactions are called as functionalization reactions. Phase I reactions are Non-synthetic in nature. The majority of Phase I metabolites are generated by a common hydroxylating enzyme system known as cytochrome P450. 03-12-2010 KLECOP, Nipani 15
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Oxidative reaction:
1) Oxidation of aromatic carbon atoms
2) Oxidation of olefins (C=C bonds) 3) Oxidation of Benzylic, Allylic carbon atoms & carbon atoms alpha to carbonyl & imines 4) Oxidation of aliphatic carbon atoms
5) Oxidation of alicyclic carbon atoms

6) Oxidation of carbon-heteroatom systems:

A. Carbon-Nitrogen system N- Dealkylation. Oxidative deamination N-Oxide formation N-Hydroxylation
B. Carbon-Sulfur system S- Dealkylation Desulfuration S-oxidation

C. Carbon-Oxygen systems(O- Dealkylation)
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7) Oxidation of Alcohol, Carbonyle and Acid functios.

8) Miscellaneous oxidative reactions.
Reductive reactions:
1) Reduction of Carbonyl functions.(aldehydes/ketones) 2) Reduction of alcohols and C=C bonds
3) Reduction of N-compounds (nitro,azo & N-oxide)

4) Miscellaneous Reductive reactions.
Hydrolytic reactions
1) Hydrolysis of Esters and Ethers
2) Hydrolysis of Amides.
3) Hydrolytic cleavage of non aromatic heterocycles

4) Hydrolytic Dehalogination 5) Miscellaneous hydrolytic reactions.
Oxidation of aromatic carbon atoms (aromatic hydroxylation):

R OH
Arenol (major)
R R R
H2O
O
OH
epoxide hydrase
OH
Arene
Arene oxide (highly reactive electrophile) GSH 5-epoxide transferase

R OH
Dihyrdrodiol
OH
SG
OH
Tissue toxicity in instances when glutathione is depleted.
E.g. Epoxides of Bromobenzene and Benzopyrene.

Glutathione conjugate (min.pro.)
Catechol(min. Pro.)
Oxidation of olefins (C=C bonds):

Oxidation of non-aromatic C=C bonds is analogous to aromatic hydroxylation. i.e. it proceeds via formation of epoxides to yield 1,2dihydrodiols.
O HO OH
H2O
N CONH2 N CONH2
epoxide hydrase
N CONH2
Carbamazepine
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Carbamazepine-10,11 epoxide
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Trans-10,11 dihydroxy carbamazepine 22
Oxidation of Benzylic Carbon Atoms:

Carbon atoms attached directly to the aromatic ring are hydroxylated to corresponding Carbinols. If the product is a primary carbinol, it is further oxidized to aldehydes and then to carboxylic acids,
E.g.Tolbutamide
A secondary Carbinol is converted to Ketone.

CH3 CH2OH CHO COOH
Alcohol dehydrogenase
SO2NHCONHC4H9
SO2NHCONHC4H9
Tolbutamide
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Prmary carbinol
Corresponding aldehyde
Corresponding carboxylic acid.

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Oxidation of Allylic carbon Atoms:

Carbon atoms adjacent to Olefinic double bonds (are allylic carbon atoms) also undergo hydroxylation in a manner similar to Benzylic Carbons. E.g. Hydroxylation of Hexobarbital to 3`-hydroxy Hexobarbital.
Allylic carbon atom 3' 2'
H3C O O H3C O O OH
HN
N CH3 O
HN
N CH3 O
Hexobarbital
3'-Hydroxy Hexobarbital
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Oxidation of Carbon Atoms Alpha to Carbonyls and Imines:

Several Benzodiazepines contain a carbon atom (C-3) alpha to both Carbonyl (C=0) and imino (C=N) function which readily undergoes Hydroxylation.
E.g. Diazepam
O N N
3
N IC IC N
OH
Diazepam
3-Hydroxy diazepam
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Oxidation of Aliphatic Carbon Atoms (Aliphatic Hydroxylation):
Terminal hydroxylation of methyl group yields primary alcohols which undergoes further oxidation to aldehydes and then to carboxylic acid.
H CH3 C H2 C H COOH H3C OH C CH3 C H2 CH3 C H COOH
H3C
C CH3
Ibuprofen
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Tertiary alcohol metabolite

26
Oxidation of Alicyclic Carbon Atoms (Alicyclic Hydroxylation):

Cyclohexane (alicyclic) and piperidine (non-aromatic heterocyclic) rings are commonly found in a number of molecules. E.g. Acetohexamide and minoxidil respectively. Such rings are generally hydroxylated at C-3 or C-4 positions.
H2N N H2N N N
4'
OH
H2N
H2N
Minoxidil
4'-Hydroxy Minoxidil
27
Oxidation of Carbon-Heteroatom Systems:

Biotransformation of C-N, C-0 and C-S system proceed in one of the two way: 1. Hydroxylation of carbon atom attached to the heteroatom and subsequent cleavage at carbonheteroatom bond. E.g. N-, O- and S- dealkylation, oxidative deamination and desulfuration. 2. Oxidation of the heteroatom itself.
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E.g. N- and S- oxidation.
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Oxidation of Carbon-Nitrogen System:
N-Dealkylation:
Mechanism of N-dealkylation involve oxidation of carbon to generate an intermediate carbinolamine which rearranges by cleavage of C-N bond to yield the N dealkylated product and the corresponding carbonyl of the alkyl group.
H N OH O
C
H
C
H
NH
+ Carbonyl
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Carbinolamine Intermediate KLECOP, Nipani
N-Dealkylated metabolite
29
A tertiary nitrogen attached to different alkyl groups undergoes dealkylation by removal of smaller alkyl group first.
Example:
Secondary aliphatic amine E.g. Methamphetamine. Tertiary aliphatic amine Tertiary alicyclic amine Amides
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E.g. imipramine E.g. hexobarbital E.g. Diazepam
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N-Hydroxylation:-
Converse to basic compounds that form N-oxide, Nhydroxy formation is usually displayed by non-basic nitrogen atoms such as amide Nitrogen.
E.g. Lidocaine
CH3 O N H C C H2 N C2H5 CH3 CH3 C2H5 N OH CH3 O C C H2 N C2H5 C2H5
Lidocaine
N- Hydroxy Lidocaine
31
Oxidation of Carbon-Sulfur Systems:

S-Dealkylation: The mechanism of S-Dealkylation of thioethers is analogous to N-dealkylation .IT proceed via -carbon hydroxylation. The C-S bond cleavage results in formation of a thiol and a carbonyl product. E.g. 6-Methyl mercaptopurine.
SCH3 N SCH2OH N N N SH N N N N N H N
+ HCHO
N H
N H
6-Methyl Mercaptopurine 03-12-2010
Hydroxylated intermediate
6-Mercaptopuri9ne
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Desulfuration:
This reaction also involves cleavage of carbon-sulfur bond (C=S). The product is the one with C=0 bond. Such a desulfuration reaction is commonly observed in thioamides such as thiopental.
Thiopental
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Pentobarbital
33
S-Oxidation:
Apart from S-dealkylation, thioethers can also undergo Soxidation reaction to yield sulfoxides which may be further oxidized to sulfones several phenothiazines. E.g. Chlorpromazine undergo S-oxidation.
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Oxidation of Carbon-Oxygen Systems:

O-Dealkylation: This reaction is also similar to N-Dealkylation and proceeds by -carbon hydroxylation to form an unstable hemiacetal or hemiketal intermediate. Which spontaneously undergoes C-0 bond cleavage to form alcohol and a carbonyl moiety.
OH H
R-O-CH2R' Ether
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R-O-CH-R' Hemiacetal
R-OH Alcohol
O=C-R' Aldehyde/ketone
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Oxidation of Alcohol, Carbonyl and Carboxylic Acid

In case of ethanol, Oxidation to acetaldehyde is reversible and further oxidation of the latter to acetic acid is very rapid since Acetaldehyde is highly toxic and should not accumulate in body.
alcohol CH3CH2OH dehydrogenase Ethanol

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Aldehyde CH3CHO Acetaldehyde

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CH3COOH dehydrogenase Aceticacid

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Miscellaneous oxidative reactions:

Oxidative aromatization /dehydrogenation:
E.g. Metabolic aromatization of drugs is nifedipine.
COOCH3 NO2 CH3 NH CH3 COOCH3 Nitedipine
COOH NO2 CH2OH N CH3 COOCH3 Pyridine metabolite

37
Oxidative Dehalogenation:
This reaction is common with halogen containing drugs such as chloroform.
Dehalogenation of this drug yields phosgene which may results in electrophiles capable of covalent binding to tissue.
Cl Cl H Cl
oxi. -HCL
O Cl Cl
Covalent binding to tissues.
Chloroform
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Phosgene
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Reductive reaction:
Bioreductions are also capable of generating polar functional group such as hydroxy and amino which can undergo further biotransformation or conjugation. Reduction of carbonyls: Aliphatic aldehydes : E.g. Chloral hydrate
Cl3C-CHOH2O Chloral hydrate
Cl3C-CH2OH
Trichloroethan
39
Aliphatic ketones:
O C 2H 5 H 2C H C N CH 3 CH 3
E.g. Methadone.
OH C 2H 5 H 2C H C N CH 3 CH 3
H 3C Methadone
H 3C Methadol
Aromatic Ketone:
O CH 3
E.g. Acetophenone.
OH C H CH 3
Acetophenone
Methyl phenyl carbinol

40
Reduction of alcohols and C=C:

These two reductions are considered together because the groups are interconvertible by simple addition or loss of a water molecule. Before an alcohol is reduced it is dehydrated to C=C bond.
Example bencyclane . (antispasmodic)
(CH2)3 N(CH3)2
OH Bencyclanol
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Bencyclane
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Benzylidine cycloheptane
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Reduction
of N-compounds:
Reduction of nitro groups proceeds via formation of nitro so and hydroxyl amine intermediates to yield amines.
RNO2 Nitro
For
R-N=O Nitroso
R-NHOH
RNH2 Amine
Hydroxylamine
E.g. Reduction of Nitrazepam.

H N N O H N N O
O 2N
H 2N
Nitrazepam
7-Amino metabolite.
42
Reduction of azo compounds yield primary amines via formation of hydrazo intermediate which undergo cleavage at N-N bond.
R-N=N-R' Azo E.g. Prontosil.
NH2 H2N N N
R-NH-NH-R' Hydrazo
NH2
RNH2
NH2R'
Amines
SO2NH2
H2N
NH2
H2N
SO2NH2
Prontosil
1,2,4-Triamino benzene sulfanilamide
It is reduced to active Sulfanilamide.

Miscellaneous reductive reactions:

Reductive Dehalogenation: This reaction involves replacement of halogen attached to the carbon with the H-atom. E.g. Halothane.
Br CF 3 Cl Halothane 1,1,1- Trifluroethane H CF 3-CH3 CF 3-COOH
Trifluroacetic ac
Reduction of sulfur containing functional groups:

C2H5 C2H5 Dsulfiram
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S N S S
S N
C2H5 C2H5
C2H5 C2H5
S N SH
E.g. Disulfuram
Diethyldithiocarbamic acid
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Hydrolytic
reactions:
1. The reaction does not involve change in the state of oxidation of substrate. 2. The reaction results in a large chemical chain in the substrate brought about by loss of relatively large fragments of the molecule.
Hydrolysis of esters and ethers:

Esters on hydrolyisis yield alcohol and carboxylic acid. The reaction is catalyzed by esterases.
O R-C-OR'
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O R-C-OH
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R'-OH
45
Organic acid esters:

Esters with a large acidic group :
COOC2H5
Cl O CH3 Cl O
E.g. Clofibrate
COOH
CH3
CH3 Clofibrate
CH3
C2H5OH
Free acid metan
Esters with a large acidic and alcoholic group:
E.g. Succinylcholine
H2C COOCH2CH2-N(CH3)2 Pseudo CH2COOH CH2COOH
HOCH2CH2N(CH3)2
C COOCH2CH2-N(CH3)2 CholineH2 sterase Suceinylcholine

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succinic acid
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choline
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Inorganic acid esters:

Phosphates:
OH O P O OH C 2H5 C 2H5 OH O P O OH HO C 2H5
E.g. Stilbestrol diphosphate

C 2H5 OH
2 H3PO4
Stilbestrol diphosphate
stilbestrol
Sulfates:
CH3 H3C H O O S CH3 O
E.g. Isopropyl methanesulfonate

CH3 H3C H isopropanol OH O
HO S CH3 O
Isopropyl methnesulfonate
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methanesulfonic a
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Hydrolysis
of amides:
The reactions catalyzed by amides, involves C-N cleavage to yield carboxylic acid and amine.
O R-C-NHR' O R-C-OH
R'NH2
primary amide with aliphatic substituent on N-atom:

E.g. Procainamide
O H2N
C2H5
N C C N H H2 H2 C2H5 H2N
C2H5
+
OH
H2N
C C N C2H5 H2 H2
Procanamide
PABA
48
Secondary amide with aromatic Substituent on N-atom:

E.g. Lidocaine
CH3 O N H CH3 CH3
C2H5
C N H2 C2H5 NH2 CH3
C2H5
HOOC
C N C2H5 H2
Lidocaine
2,6 Xylidine
N, N- Diethylglycin
Tertiary amide:
E.g. Carbamazepine
N CONH2 Carbamazepine
N H Iminostilbene
49
Hydrolytic cleavage of non aromatic heterocyclics:

Four membered lactams:
O C H2 H N
E.g. Penicillins
O C H2 H N
S N
CH 3 CH3
S N O
CH 3 CH 3
HO
COOH
Penicillin G
COOH
Penicinoic acid metabolite
Five member lactams:

O N CH3 Phensuximide O
E.g. Succinimides
COOH O NH2
Phenyl succinamic acid
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Hydrolytic
dehalogenation:
Chlorine atoms attached to aliphatic carbons are dehalogenated easily. E.g. Dichloro diphenyl trichloro ethane
H Cl CCl 3
-HCL Cl
Cl
Cl
CCl 2
DDT
DDE
Miscellaneous hydrolytic reactions: Include hydration of epoxides and arene oxides, hydrolysis of Sulfonylureas, Carbamates, Hydroxamates and alpha Glucuronide and sulfate conjugates
Phase 2 Reactions
Synthetic Conjugation
Phase II
Phase II - combines functional group of compound with endogenous substance E.g. Glucuronicacid, Sulfuric acid, Amino Acid, Acetyl. Products usually very hydrophilic The final compounds have a larger molecular weight.
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Enzymes
Glucuronosyl Transferases Sulfotransferases (ST) Acetyltransferase Methylases
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How We Get To Phase 2

Most of the drugs do not become polar upon phase 1 reactions. The Body is left with a plan to further metabolize the Drugs Goal of Phase 2 : Make substances more soluble that couldnt be done in the Phase 1 reactions.
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Synthetic Reactions / Phase II

These reactions usually involves covalent attachments of small polar endogenous molecules such as Glucoronic acid, Sulfate, Glycine to either unchanged drugs or Phase I product having suitable functional groups as COOH,-OH,-NH2,- SH. Thus is called as Conjugation reactions. Since the product formed is having high molecular weight so called as synthetic reactions. The product formed is hydrophilic in nature with total loss of pharmacologic activity so called as a true detoxification reaction
Phase II
Glucuronide Conjugation Methylation Acetylation Sulfate Conjugation Conjugation With Alpha Amino Acids Glutathione Conjugation Glycine Conjugation Cyanide Conjugation
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Very important Synthetic reactions carried out by Uredine Di Phosphate Glucuronosyl Transferase. Hydroxyl and Carboxylic acid groups are easily combined with Glucuronic acid.
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Glucuronide formation occurs in 2 steps:-
1. Synthesis of an activated coenzyme uridine-5- diphospho -alphaD- Glucuronic acid (UDPGA) from UDP- glucose (UDPG). -D-Glucose-1-phosphate + UTP
Pyrophosphorylase
UDPG + Ppi
UDPG - Dehydrogenase
UDPG +2NAD + H2O
UDPGA +2NADH + 2H+
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2. Transfer of the glucuronyl moiety from UDPGA to the substrate RXH in presence of enzyme UDPUDP-Glucuronyl transferase glucuronyl transferase to form the conjugate.
UDPGA + RXH
Where, X = O, COO, NH or S
RX Glucuronic Acid +UDP
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COOH
OH
COOH
COOH Benzoic acid OH
OH
OH
UDP
UDPGA Benzoic Acid
OH
OH Glucuronide Benzoic acid
Ex.
Chloramphenicol, Morphine, Salicylic Acid, Paracetamol
Common, minor pathway. Methyltransferases -CH3 transfer to O, N, S, C
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1. Synthesis of an activated coenzyme S- adenosyl methionine(SAM), the donor of methyl group, from Lmethionine and ATP. L Methionine + ATP
Methionine Adenosyl Transferase
SAM + PPi + Pi
2. Transfer of the methyl group from SAM to the substrate in presence of nonmicrosomal enzyme methyl transferase.
RXH + SAM RX-CH3 + S Adenosyl Homocysteine
Methyl Transferase
Ex.
Morphine, Nicotine, Histamine
Major route of biotransformation for aromatic amines, hydrazine. Generally decreases water solubility Enzyme: - N- Acetyltransferase (NAT)
R NH2
R NH COCH3
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COOH OH
COOH OH
CH3COSCOA
NH 2
Paraaminosalicyclic Acid
Acetyl Co enzyme
NHCOCH3
NH 2 N- Acetylated PAS
Ex. Histamine, PAS, PABA

Sulfotransferases are widely-distributed enzymes Cofactor is 3-phosphoadenosine-5-phosphosulfate (PAPS) Produce highly water-soluble sulfate esters, eliminated in urine, bile R OH R O SO3
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1. Synthesis of an activated coenzyme 3-phosphoadenosine-5phosphosulfate (PAPS) which acts as a donor of sulfate to the substrate. This also occurs in two steps- an initial interaction between the sulfate and the adenosine triphosphate (ATP) to yield adenosine-5-phosphosulfate (APS) followed by activation of latter to PAPS.
ATP Sulfurylase/Mg++ ATP + SO42APS Phosphokinase/Mg++

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APS + Ppi
APS + ATP
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PAPS + ADP
2. Transfer of sulfate group from PAPS to the substrate RXH in presence of enzyme Sulfotransferase and subsequent liberation of 3- phosphoadenosine-5-phosphate(PAP). PAPS + RxH Rx-SO3 + PAP
Sulfotransferase
X= O,NH
Examples of compounds undergoing sulfation are: Phenol Paracetamol , Salbutamol Alcohols Aliphatics C-1 to C-5 Arylamines Aniline
Alternative to glucuronidation Two principle pathways -COOH group of substrate conjugated with -NH2 of Glycine, Serine, Glutamine, requiring CoA activation E.g. conjugation of benzoic acid with Glycine to form Hippuric acid Aromatic -NH2 or NHOH conjugated with -COOH of Serine, Proline, requiring ATP activation
1. Activation of carboxylic acid drug substrate with ATP and coenzyme A (CoA) to form an acyl CoA intermediate. Thus, the reaction is a contrast of glucuronidation and sulfation where the donor coenzyme is activated and not the substrate.
Acetyl Synthetase RCOOH + ATP RCOAMP + H2O + Ppi
Acyl CoA Transferase
RCOAMP + CoA-SH
RCSCoA + AMP
2. Acylation of the alpha- amino acid by the acyl CoA in presence of enzyme N-acyl transferase. RCSCoA + NH2-R-COOH
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N-Acetyl transferase
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RCONH-RCOOH + CoA- SH
70
Glutathione-S-transferase catalyzes conjugation with glutathione Glutathione is tripeptide of Glycine, Cysteine, Glutamic
acid
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Glutathione-S-transferase
-Glutamyl
transferase
Glycine
Cysteinyl glycinase
N- acetylase
Mercapturic Acid Derivative

Glycine Conjugation
Salicylates and other drugs having carboxylic acid group
are conjugated with Glycine. Not a major pathway of metabolism
Cyanide Conjugation
Conjugation of cyanide ion involves transfer of sulfur atom from thiosulfate to the cyanide ion in presence of enzyme rhodanese to form inactive thiocyanate.
S2O3 + CN
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2-
rhodanese
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SCN + SO3
274
Biotransformation-Conclusion
Change the Xenobiotics to a form that can be eliminated from the body Change the Xenobiotics to a less biologically active form Bioactivation to more toxic forms can also occur Synthetic Phase II reactions are carried out by other enzymes.
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Factor affection of
Biotransformation of drug:
The Therapeutic efficacy, Toxicity and Biological half life of drug depends on metabolic rate and the factor that influence metabolic rate are: 1) Physicochemical property of drug. 2) chemical factors:
a. Induction of drug metabolizing enzyme. b. Inhibition of drug metabolizing enzyme c. Environmental chemicals.
3) Biological factors. A. Species differences. B. Strain differences. C. Sex differences.
D. Age. E. Diet. F. Altered pharmacologic factors:
i Pregnancy. ii Hormonal imbalance. iii Disease state.

G. Temporal factors: I Circadian rhythm.
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References
Biopharmaceutics & Pharmacokinetics by D.M. Brahmankar, S. B. Jaswal, Vallabh Prakashan, Pg111-158. Biopharmaceutics & Pharmacokinetics by Milo Gibaldi, 4th edition, Pg.no. 203. Text book of Biopharmaceutics & pharmacokinetics, Dr.Sobha Rani R. Hiremath, Prism Books Pvt Ltd, Bangalore, 2000 Pg.no. 157-166. www.google.com www.pharmacology.com
Cell No: 0091 9742431000 E-mail: bknanjwade@yahoo.co.in


Bio Rans Formation

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Bio Rans Formation

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BIOTRANSFORMATION

Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

Contents:Introduction Phase I reaction Phase II reaction Factors affecting Biotransformation Reference

Pharmacologic Inactivation of Drug

Active Metabolite From An Inactive Drug

No Change in Pharmacologic Activity

Active Drug Morphine

Drug metabolizing organs

Drug Metabolizing Enzymes

Synthetic/ Phase II reactions

ONLY Glucuronide conjugation

When and How?

5) Oxidation of alicyclic carbon atoms

6) Oxidation of carbon-heteroatom systems:

B. Carbon-Sulfur system S- Dealkylation Desulfuration S-oxidation

7) Oxidation of Alcohol, Carbonyle and Acid functios.

3) Reduction of N-compounds (nitro,azo & N-oxide)

3) Hydrolytic cleavage of non aromatic heterocycles

Oxidation of aromatic carbon atoms (aromatic hydroxylation):

Arene oxide (highly reactive electrophile) GSH 5-epoxide transferase

Tissue toxicity in instances when glutathione is depleted.

E.g. Epoxides of Bromobenzene and Benzopyrene.

Glutathione conjugate (min.pro.)

Oxidation of olefins (C=C bonds):

Trans-10,11 dihydroxy carbamazepine 22

Oxidation of Benzylic Carbon Atoms:

A secondary Carbinol is converted to Ketone.

Corresponding carboxylic acid.

Oxidation of Allylic carbon Atoms:

Oxidation of Carbon Atoms Alpha to Carbonyls and Imines:

Oxidation of Aliphatic Carbon Atoms (Aliphatic Hydroxylation):

Tertiary alcohol metabolite

Oxidation of Alicyclic Carbon Atoms (Alicyclic Hydroxylation):

Oxidation of Carbon-Heteroatom Systems:

E.g. N- and S- oxidation.

Oxidation of Carbon-Nitrogen System:

Carbinolamine Intermediate KLECOP, Nipani

E.g. imipramine E.g. hexobarbital E.g. Diazepam

Oxidation of Carbon-Sulfur Systems:

6-Methyl Mercaptopurine 03-12-2010

Oxidation of Carbon-Oxygen Systems:

Oxidation of Alcohol, Carbonyl and Carboxylic Acid

alcohol CH3CH2OH dehydrogenase Ethanol

Aldehyde CH3CHO Acetaldehyde

CH3COOH dehydrogenase Aceticacid

Miscellaneous oxidative reactions:

COOH NO2 CH2OH N CH3 COOCH3 Pyridine metabolite

Covalent binding to tissues.

Methyl phenyl carbinol

Reduction of alcohols and C=C:

Example bencyclane . (antispasmodic)

E.g. Reduction of Nitrazepam.

1,2,4-Triamino benzene sulfanilamide

It is reduced to active Sulfanilamide.

Miscellaneous reductive reactions:

Reduction of sulfur containing functional groups:

Hydrolysis of esters and ethers:

Organic acid esters:

Free acid metan

Esters with a large acidic and alcoholic group:

C COOCH2CH2-N(CH3)2 CholineH2 sterase Suceinylcholine

Inorganic acid esters:

E.g. Stilbestrol diphosphate