biotransformation of drug
Biotransformation/Xenobiotic metabolism/ drug metabolism/detoxification.
-Xenobiotics: a wide variety of foreign compounds to which humans get exposed in day to day life.
-It includes unknown compounds, drugs, environmental pollutants, toxins.
-Many xenobiotics can evoke biological responses.
DEFINITION
The biochemical alteration of drug or xenobiotic in the presence of various enzymes that acts as a catalyst which themselves not consumed in the reaction and there by may activate or deactivate the drug is called biotransformation.
Why Biotransformation is necessary?:
To easily eliminate the drug
To terminate drug action by inactivating it
Consequences of Biotransformation
Active to Inactive:
Phenobarbitone---- Hydroxyphenobarbitone
Inactive (prodrug) to Active :
L-Dopa ---- Dopamine
Parathion -- Paraoxon
Talampicillin -- Ampicillin
Active to equally active:
Diazepam -- Oxazepam
Amitriptyline -- Nortriptyline
Imipramine -- Des-imipramine
Codeine -- Morphine
Sites of biotransformation
In the body: Liver, small and large intestines, lungs, skin, kidney, nasal mucosa & brain.
Liver is considered “metabolite clearing house” for both endogenous substances and xenobiotics.
Intestines are considered “initial site of drug metabolism”.
FIRST PASS METABOLISM:
First pass metabolism or presystemic
metabolism or ‘first pass effect’
After oral administeration many drugs are absorbed from the small intestine - transported first via portal system to the liver, where they undergo extensive metabolism before reaching systemic circulation.
fundamental concepts in drug biotransformation
Lipid soluble drugs are poorly excreted in the urine. They tend to store in fat and/or circulate until they are converted (phase I biotransformation) to more water soluble metabolites or metabolites that conjugate (phase II biotransformation) with water soluble substances.
Water soluble drugs are more readily excreted in the urine. They may be metabolized, but generally not by the CYP enzyme systems.
Enzymes catalyzing phase I biotransformation reactions
Enzymes catalyzing phase I biotransformation reactions include:
cytochrome P-450
aldehyde and alcohol dehydrogenase
deaminases
esterases
amidases
epoxide hydratases
Addition of water
Cleavage of R-O or R-N bond accompanied by addition of H2O
CYTOCHROME P450
The cytochrome P-450 families are referred to using an arabic numeral, e.g., CYP1, CYP2, etc.
Each family has a number of subfamilies denoted by an upper case letter, e.g., CYP2A, CYP2B, etc.
The individual enzymes within each subfamily are denoted by another arabic numeral, e.g., CYP3A1, CYP3A2, etc.
Metabolic Changes of Drugs and Related Organic Compounds describes the human metabolic processes of various functional groups found in therapeutic agents.
The importance of a chapter on metabolism lies in the fact that drug interactions are based on these processes.
For pharmacists, it is necessary for them to understand why certain drugs are contraindicated with other drugs.
This chapter attempts to describe the various phases of drug metabolism, the sites where these biotransformation will occur, the role of specific enzymes, metabolism of specific functional groups, and several examples of the metabolism of currently used therapeutic agents.
Phase I Vs Phase II Drug metabolism and factors affectiing drug metabolism.
Enzyme induction, Enzyme inhibitor, physicochemical properties wthich acan affect the drug metabolism
Metabolic Changes of Drugs and Related Organic Compounds describes the human metabolic processes of various functional groups found in therapeutic agents.
The importance of a chapter on metabolism lies in the fact that drug interactions are based on these processes.
For pharmacists, it is necessary for them to understand why certain drugs are contraindicated with other drugs.
This chapter attempts to describe the various phases of drug metabolism, the sites where these biotransformation will occur, the role of specific enzymes, metabolism of specific functional groups, and several examples of the metabolism of currently used therapeutic agents.
Phase I Vs Phase II Drug metabolism and factors affectiing drug metabolism.
Enzyme induction, Enzyme inhibitor, physicochemical properties wthich acan affect the drug metabolism
Adventures in Metabolite Profiling with an Accurate Mass QTofMicroConstants
Presentation given by David Johnson, Ph.D., Director of DMPK and MicroConstants, during the Waters Applications of Time of Flight Spectrometry Seminar in Long Beach in September 2010. The presentation provides a brief background on drug metabolism, discusses the relevance of metabolite profiling, and reviews a metabolite profiling workflow.
pharmacokinetics- action of body on the drug. includes absorption, dissolution, metabolism and excretion of drug. In this presentation metabolism and excretion of the drug are covered . Includes conversion of lipophilic / non-water soluble compounds into easily removable compounds by the action of hepatic enzymes which can be microsomal or non-microsomal . Excretion is further removal or elimination of compounds or agents from the body. Drug elimination is the sum of the processes of removing an administered drug from the body. In the pharmacokinetic ADME scheme (absorption, distribution, metabolism, and excretion), it is frequently considered to encompass both metabolism and excretion. Hydrophobic drugs, to be excreted, must undergo metabolic modification making them more polar. Hydrophilic drugs, on the other hand, can undergo excretion directly, without the need for metabolic changes to their molecular structures. Introduction
Most drugs are xenobiotics, ie, chemical substances not naturally produced by the body. Xenobiotics undergo various body processes for detoxification, thus reducing their toxicity and allowing them to be readily available for excretion. These processes allow for the chemical modification of drugs into their metabolites and are known as drug metabolism or metabolic biotransformation.
These metabolites are the byproducts of drug metabolism and can be characterized by active, inactive, and toxic metabolites. Active metabolites are biochemically active compounds with therapeutic effects, whereas inactive metabolites are biochemically inactive compounds with neither a therapeutic nor toxic effect. Toxic metabolites are biochemically active compounds similar to active metabolites but have various harmful effects.
Drug metabolism occurs at a specific location in the body, resulting in a low concentration of active metabolites in the systemic circulation. This phenomenon is called first-pass metabolism because it limits drug bioavailability. First-pass metabolism primarily occurs in the liver; however, metabolizing enzymes can be found throughout the body.
Understanding these alterations in chemical activity is crucial in utilizing the optimal pharmacological intervention for any patient. This is a topic of interest to any provider who routinely treats patients with medications. The metabolism of pharmaceutical drugs is an important aspect of pharmacology and medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer, and the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down or not is covered.pharmacokinetic
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
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3. DEFINITION
• The biochemical alteration of drug or
xenobiotic in the presence of various enzymes
that acts as a catalyst which themselves not
consumed in the reaction and there by may
activate or deactivate the drug is called
biotransformation.
3
4. Why Biotransformation is
necessary?:
• To easily eliminate the drug
• To terminate drug action by inactivating it
By changing its physicochemical properties
from:
4
Active /inactive
Lipophilic
Unionised
Nonpolar
Plasma protein
bound
Inactive /active
Hydrophilic
Ionised
Polar
Free
5. Consequences of
Biotransformation
• Active to Inactive:
Phenobarbitone----
Hydroxyphenobarbitone
• Inactive (prodrug) to Active :
L-Dopa ---- Dopamine
Parathion -- Paraoxon
Talampicillin -- Ampicillin
5
6. • Active to equally active:
Diazepam -- Oxazepam
Amitriptyline -- Nortriptyline
Imipramine -- Des-imipramine
Codeine -- Morphine
6
7. Sites of
biotransformation
• In the body: Liver, small and large intestines,
lungs, skin, kidney, nasal mucosa & brain.
• Liver is considered “metabolite clearing house”
for both endogenous substances and
xenobiotics.
• Intestines are considered “initial site of drug
metabolism”.
7
8. FIRST PASS METABOLISM:
• First pass metabolism or presystemic
metabolism or ‘first pass effect’
• After oral administeration many drugs are
absorbed from the small intestine -
transported first via portal system to the
liver, where they undergo extensive
metabolism before reaching systemic
circulation.
8
10. fundamental concepts in drug
biotransformation
Lipid soluble drugs are poorly excreted in the urine.
They tend to store in fat and/or circulate until they
are converted (phase I biotransformation) to more
water soluble metabolites or metabolites that
conjugate (phase II biotransformation) with water
soluble substances.
Water soluble drugs are more readily excreted in the
urine. They may be metabolized, but generally not
by the CYP enzyme systems.
10
22. Hydrolysis
• Addition of water
– Cleavage of R-O or R-N bond accompanied by addition of
H2O
22
Ether
Amide
R
O
R'
+ H2O R OH HO R'+
R
N
R'
+ H2O R N HO R'+
H
H
H
26. 26
CYTOCHROME P450
The cytochrome P-450 families are referred to using an arabic numeral, e.g., CYP1,
CYP2, etc.
Each family has a number of subfamilies denoted by an upper case letter, e.g., CYP2A,
CYP2B, etc.
The individual enzymes within each subfamily are denoted by another arabic
numeral, e.g., CYP3A1, CYP3A2, etc.
28. • When phase I reactions are not producing sufficiently hydrophilic (water
soluble) or inactive metabolites to be eliminated from the body, the
drugs or metabolites formed from phase I reaction undergoes phase II
reactions.
• Generally phase I reactions provide a functional groups or handle in the
molecule that can undergo phase II reactions. Thus, phase II reactions
are those in which the functional groups of the original drug (or
metabolite formed in a phase I reaction) are masked by a conjugation
reaction.
• Phase II conjugation reactions are capable of converting these
metabolites to more polar and water soluble products.
• Many conjugative enzymes accomplish this objective by attaching small,
polar, and ionizable endogenous molecules such as glucuronic acid ,
sulfate, glycine, glutamine and glutathione to the phase I metabolite or
parent drug. The resulting conjugated products are very polar (water
soluble), resulting in rapid drug elimination from the body. 28
PHASE 2 REACTIONS
29. • These reactions require both a high-energy molecule and an
enzyme.
• The high-energy molecule consists of a coenzyme which is bound
to the endogenous substrate and the parent drug or the drug’s
metabolite resulted from phase I reaction.
• The enzymes that catalyzed conjugation reactions are called
transferases, found mainly in the liver and to a lesser extent in the
intestines and other tissues.
• Most conjugates are biologically inactive and nontoxic because
they are highly polar and unable to cross cell membrane.
• Exceptions to this are acetylated and methylated conjugates
because these phase II reactions (methylation and acetylation)
does not generally increase water solubility but serve mainly to
terminate or reduce pharmacological activity (they are usually
pharmacologically inactive).
29
30. CONJUGATION MOLECULES:
• 1- Glucuronic acid conjugation:
• It forms O-glucuronides with phenols Ar-OH, alcohols R-
OH, hydroxylamines H2N-OH,and carboxylic acid RCOOH.
• It can form N-glucuronides with sulfonamides, amines,
amides, and S-glucuronides with thiols.
• 2-Sulfate conjugation:
• It is less common.
• It is restricted to phenols, alcohols, arylamines, and N-
hydroxyl compounds.
• But primary alcohols and aromatic hydroxylamines can
form unstable sulfate conjugates which can be toxic.
30
31. • 3-Amino acid conjugation:
• By the formation of peptide link. With glycine
or glutamine.
• 4- Glutathione conjugation:
• It reacts with epoxides, alkylhalides,
sulfonates, disulfides, radical species.
• These conjugates are converted to
mercapturic acid and mostly are excreted in
bile. It is important in detoxifying potentially
dangerous environmental toxins.
31
32. • 5,6- Methylation and acetylation reactions:
• These decrease the polarity of the drugs except tertiary
amines which are converted to polar quaternary salts.
• The groups susceptible for these reactions are phenols,
amines, and thiols.
• O-methylation of meta-phenolic OH in catecholamines
• does not generally increase water solubility but serve
mainly to terminate or reduce pharmacological activity
(they are usually pharmacologically inactive).
• 7- Cholesterol conjugation:
• For carboxylic acids by ester link formation or for drug
with ester group by trans esterification.
• 8- Fatty acid conjugation:
• For drugs with alcohol functional groups by ester link
32
33. There are six conjugation pathways:
O
HO
HO
HOOC
H
O UDPOH
R X+
O
HO
HO
HOOC
H
XOH R
X = OH, NR2, CO2H, SH, acidic carbon atomGlucuroinc acid UDP
O
Adenine
P
O
OS
O
HO
O OH
HOH2O3PO
PAPS
+ R X S X
O
HO
RO
X = OH, arylamine, NHOH
Glucuronyl Transferease catalyses this conjugation reaction
Sulfotransferease catalyses this conjugation reaction
33
34. 34
There are six conjugation pathways:
C
S
CoA
O
R
+
H2N CO2H
Y
H
N CO2H
Y
H
C
R
O
H
Y = H or CH2CH2CO2H
Acyl coenzyme A
N-acyltransferase catalyses the conjugation reaction
C
S
CoA
O
R
+
H2N CO2H
Y
H
N CO2H
Y
H
C
R
O
H
Y = H or CH2CH2CO2H
Acyl coenzyme A
Glutathione S-transferase catalyses this conjugation
reaction
35. 5)-Methylation
N-acyltransferase catalyses the conjugation reaction
Methyltransferase catalyses this conjugation reaction
O
Adenine
S
+
NH2
HO2C
CH3
HOH2O3PO
R X+ R X CH3
SAM
X = OH, NH2, SH
Aceyl CoA
Y =NH2, NHNH2, SO2NH2, CONH2
R
X
C
R
O
+C
S
CoA
O
H3C
R X
35
36. Non-Enzymatic Biotransformation
• Skeletal muscle relaxants like ATRACURIUM
are metabolised in the plasma spontaneously
through molecular rearrangement without
involvement of any enzyme action.
36
37. FACTORS AFFECTING BIOTRANSFORMATION OF
DRUGS
1. Physicochemical properties of the drug
2. Chemical factors
a. Induction of drug metabolising enzymes
b. Inhibition of drug metabolising enzymes
c. Environmental chemicals
3. Biological factors
a. Species differences
b. Strains differences
c. Sex differences
d. Age
e. Diet
f. Altered physiological factors: (pregnancy, hormonal
imbalance, disease states)
g. Temporal factors: ( circadian rhythm, circannual rhythm)
37
38. Induction of Drug Metabolism
• Enzyme induction is the process by which exposure to certain
substrates (e.g., drugs, environmental pollutants) results in
accelerated biotransformation with a corresponding reduction
in unmetabolized drug.
• Many currently used drugs are well known to induce their
own metabolism or the metabolism of other drugs. Some
examples are the anticonvulsant medications phenobarbital
and carbamazepine
• Cigarette smoking can cause increased elimination of
theophylline and other compounds.
38
39. Consequences of Induction
• Increased rate of metabolism
• Decrease in drug plasma concentration
• Enhanced oral first pass metabolism
• Reduced bioavailability
• If metabolite is active or reactive, increased drug effects or
toxicity
39
Therapeutic Implications of Induction
-Most drugs can exhibit decreased efficacy due to rapid
metabolism
but drugs with active metabolites can display increased
drug effect and/or toxicity due to enzyme induction
-Dosing rates may need to be increased to maintain
effective plasma concentrations
40. Inhibition of Drug Metabolism
• Drug metabolism is an enzymatic process can
be subjected to inhibition.
• Drugs and other substances can inhibit the
metabolism of other drugs.
40
41. Some types of inhibition
• Competition between substrates for enzyme active site
Concentration of substrates
Affinity for binding site (drug with hi affinity for an
enzyme will slow the metabolism of any low affinity
drug)
• Irreversible inactivation of enzyme
Complex with heme iron of CYP450 (cimetidine,
ketoconazole)
Destruction of heme group (secobarbital)
• Depletion of cofactors such as NADH2 for phase II
enzymes
41
42. Consequences of Inhibition
• Increase in the plasma concentration of
parent drug
• Reduction in metabolite concentration
• Exaggerated and prolonged
pharmacological effects
• Increased liklihood of drug-induced
toxicity
42
43. Therapeutic Implications of Inhibition
• May occur rapidly with no warning
• Particularly effects drug prescribing for
patients on multidrug regimens
• Knowledge of the CYP450 metabolic pathway
provides basis for predicting and
understanding inhibition
43
44. 44
Reference
a. Milo gibaldi, Biopharmacetics and clinical
pharmacokinetics, 4th edition, page No:213-230
b. Leon shargel,susanna wu-pong,Andrew.B.C.YU,
Applied biopharmaceutics & pharmacokinetics,5th
edition, page No:303-347
c.D.M.Brahmankar,Sunil.B.Jaiswal, Biopharmaceutics
& pharmacokinetics A Treatise, 2nd edition, page No:
139-192
d. CVS Subrahmanyam, Text book of biopharmaceutics
& pharmacokinetics-concepts & applications,1st edition
2010, page No:339-364