Biotransformation Bds
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Fate of the drug
Dr.U.P.Rathnakar K.M.C. Mangalore.
MD.DIH.PGDHM
Biotransformation:Metabolism
Chemical alteration of the drug in
a living organism is called biotransformation. Lipid soluble →Water soluble So that not reabsorbed in Kidney Site-Mainly liver Others-Kidney, lungs, plasma
Metabolism: Consequences End result is usually inactivation of a drug- But intermediate product need not be! 1. Active→Inactive
Eg. Phenytoin → p-Hydroxyphenytoin 2. Active→Active Eg.Codeine → Morphine, 3. Active → Toxic. Eg. P.Mol →NABQI 4. Inactive → Active, -Prodrug Eg. Prednisone→ Prednisolone L-Dopa →Dopamine
Metabolism:Phases: I & II
Phase II (Eg.INH)
Phase I
Metabolite
Most drugs are metabolized by many pathways, simultaneously or sequentially –producing a variety of metabolites
Biotransformation Administered drug [Lipid soluble] [Non-Polar] [Lipophilic]
By
Excreted [water soluble] [Polar] [Hydrophilic]
Phase I and Phase II reactions
Catalyzed by enzymes Microsomal and Non-microsomal enzymes
Metabolism:Phase I[Non-synthetic] 1. Oxidation:
Addition of O2/Removal of H+ Eg. Phenytoin, Phenobarbitone, Propranolol 2. Reduction:
Opp.of Oxidation Eg. Choramphenicol, Methadone 3. Hydrolysis:
Addition of water Eg.Esters-Procaine, Succinylcholine, Amides- Procainamide, Lignocaine 4. Others-Cyclization and decyclization
End product active or inactive
Metabolism:Phase II(Synthetic) Conjugation of a drug or phase I metabolite with endogenous substrate –Glucuronic acid, Sulfuric acid, Acetic acid- Making it water soluble for excretion. End product usually inactive
Glucuronide conjugation Eg.Morphine, Paracetamol Acetylation
Eg.INH, Dapsone
Glycine conjugation
Eg.Salicylic acid, Nicotinic acid Eg.Sex steroids
Sulphate conjugation
Glutathione conjugation Eg.Paracetamol Methylation
Eg.Adrenaline, Dopamine
Biotransformation:Catalyzed by Enzymes Microsomal Non-Microsomal In endoplasmic reticulum
Cytoplasm, Mitochondria of liver cells and plasma
Most of Phase I and some Phase II Most of Phase II and [Glucuronide some Phase I [Some conjugation] oxidation, most reduction and Inducible hydrolysis] CYP450 Not inducible Eg. CYP2D6 Genetic polymorphism
Enzyme induction and Inhibition Induction
Inducers: Rifampicin,
Phenytoin, Barbiturate, Carbamazapine Increase synthesis of Micro enzymes→Accelerate the metabolism of substrate Rifampicin X OCP Reduced efficacy Increased toxicity-P.mol and alcoholics Beneficial –Phenobarbitone in newborn jaundice Long time
Inhibition
Inhibitors: Chloramphenicol,
Cipro, E.Mycin Warfarin & E.Mycin→Increased incidence of bleeding Quick
Factors affecting Biotransformation 1. Age-Extremes of age enzymes may be
deficient Eg.Chloramphenicol in premature babies causes Gray baby syndrome. 2. Malnutrition:- metabolism due to enz. proteins. 3.
Liver disease:- metabolism-- … so..dose of drug
4. Genetic: Genetically determined variation in metabolism Slow and fast acetylators-INH SCH
Prodrug Inactive drug Converted to active form by metabolism Improved B.A.-L-Dopa and Dopamine Prolongs duration of action- Fluphenazine Improves taste- Clindamycin palmitate Reduces ADE-Bacampicillin Methenamine release Formaldehyde in acidic urine
Drug Excretion Removal of drug and its metabolites from body Kidney Lungs Bile Feces Sweat Saliva Tears Milk
Excretion-Kidney
Renal excretion
Glomerular Filtration
Tubular secretion
Tubular reabsorption
Glomerular Filtration
Mol.size Depends on Renal blood
flow Plasma protein binding
Tubular secretion-Active Carrier mediated Not affected by PPB Penicillin, Probenecid, Quinine May use same carrier-Nonspecific Probenecid inhibits penicillin secretion
Tubular Reabsorption-Passive Depends on pH and ionization Strongly acidic and alkaline-UnionizedExcreted Weakly acidic-Ionized in alkaline medium-not absorbed. Eg. Alkaline urine and aspirin toxicity Weakly basic-Ionized in acidic urine
Eg. Acidification of urine –NH4cl or VitC-in Amphetamine poisoning
Factors affecting renal excretion
Excretion-Other routes Lungs: Alcohol, G.A, Faeces: Drugs not absorbed and secreted with bile Bile:Excreted in Bile→Reabsorbed from small intestine-This cycle is E.H.circulation
Eg.E.Mycin Skin: As and Hg Saliva: KI, phenytoin. Li Milk:Milk acidic →Alkaline drugs ionized and accumulate. Eg. Tetracycline →ADE in infant
Kinetics of Elimination Fundamental PK Parameters: 1. Vol.of distribution 2. B.A 3. Clearance
THE CLEARANCE OF A DRUG IS THE THEORETICAL VOLUME OF PLASMA FROM WHICH THE DRUG IS COMPLETELY REMOVED IN UNIT TIME Rate of elimination CL= ………………………… Plasma conc.( C)
Elimination: First and Zero Order Kinetics A constant Fraction of the drug in the body is eliminated per unit timeFirst order kinetics: Most drugs A constant Amount of the drug in the body is eliminated per unit timeZero order kinetics: Alcohol To start with First order→As the plasma concn.increases →Zero order←Enzymes get saturated……… Saturation kinetics. Eg.Phenytoin
PLASMA HALF LIFE- t1/2 It is the time required for the plasma conc. of the drug to be reduced to half of its original value
Takes 4-5 halflives to reach steady state concn. 193.5
196.5
198
187.5 175 150
93.5
96.5
98
87.5 100 75 50
100
99
199
Steady state [Plataeu principle]
Elimination First order 100 mg administered[100%] 1 t1/2 50mg 50% 2 t1/2 25mg 75% 3t1/2 12.5 mg 87.5% 4t1/2 6.25.mg 93.75% Take 4-5 halflives for complete elimination of a drug
Clinical Importance of Half Life t½ helps to determine the
duration of action of the drug. To determine the frequency
of drug administration.
To determine the time taken
to achieve the steady state.
Factors Influencing Drug dosage 4-5 half lives for steady state Short half life → repeated admn. Long half life→Takes long time to
reach steady state So loading dose is given for immediate effect Maintainance dose is given to maintain steady state
Therapeutic drug monitoring-TDM Monitoring drug therapy by measuring plasma
conc.of drugs. Indications 1. Drugs with low margin of safetyDigoxin,Lithium 2. To check Pt. compliance. 3. If individual variations are large.- TCA. 4. Potentially toxic drugs used in presence of
renal failure-AMINOGYCOSIDES 5. When Pt. does not respond without reason
Fixed Dose Combinations[FDC] Advantages Better Pt.compliance Synergistic effect
Estrogen+Progesterone Reduced side effect Aspirin+P.mol Prevents microbial resistance INH+Rifampin+PZI Improved efficacy Levodopa+Carbidopa
Disadvantages Inflexible dose ratio Incompatible PK Increased toxicity-with
wrong combinations Ignorance of contents
Eg?
How to prolong duration of action of a drug? Prolong absorption from site of administration Oral- SR tablets, CR. ?Eg Parenteral: Less soluble form, oily prep, adrenaline TTS ?Eg Increase PPB ?Eg Slow down Metabolism ?Eg Reduce Renal Excretion ?Eg
Dr.U.P.Rathnakar K.M.C. Mangalore.
MD.DIH.PGDHM
Biotransformation:Metabolism
Chemical alteration of the drug in
a living organism is called biotransformation. Lipid soluble →Water soluble So that not reabsorbed in Kidney Site-Mainly liver Others-Kidney, lungs, plasma
Metabolism: Consequences End result is usually inactivation of a drug- But intermediate product need not be! 1. Active→Inactive
Eg. Phenytoin → p-Hydroxyphenytoin 2. Active→Active Eg.Codeine → Morphine, 3. Active → Toxic. Eg. P.Mol →NABQI 4. Inactive → Active, -Prodrug Eg. Prednisone→ Prednisolone L-Dopa →Dopamine
Metabolism:Phases: I & II
Phase II (Eg.INH)
Phase I
Metabolite
Most drugs are metabolized by many pathways, simultaneously or sequentially –producing a variety of metabolites
Biotransformation Administered drug [Lipid soluble] [Non-Polar] [Lipophilic]
By
Excreted [water soluble] [Polar] [Hydrophilic]
Phase I and Phase II reactions
Catalyzed by enzymes Microsomal and Non-microsomal enzymes
Metabolism:Phase I[Non-synthetic] 1. Oxidation:
Addition of O2/Removal of H+ Eg. Phenytoin, Phenobarbitone, Propranolol 2. Reduction:
Opp.of Oxidation Eg. Choramphenicol, Methadone 3. Hydrolysis:
Addition of water Eg.Esters-Procaine, Succinylcholine, Amides- Procainamide, Lignocaine 4. Others-Cyclization and decyclization
End product active or inactive
Metabolism:Phase II(Synthetic) Conjugation of a drug or phase I metabolite with endogenous substrate –Glucuronic acid, Sulfuric acid, Acetic acid- Making it water soluble for excretion. End product usually inactive
Glucuronide conjugation Eg.Morphine, Paracetamol Acetylation
Eg.INH, Dapsone
Glycine conjugation
Eg.Salicylic acid, Nicotinic acid Eg.Sex steroids
Sulphate conjugation
Glutathione conjugation Eg.Paracetamol Methylation
Eg.Adrenaline, Dopamine
Biotransformation:Catalyzed by Enzymes Microsomal Non-Microsomal In endoplasmic reticulum
Cytoplasm, Mitochondria of liver cells and plasma
Most of Phase I and some Phase II Most of Phase II and [Glucuronide some Phase I [Some conjugation] oxidation, most reduction and Inducible hydrolysis] CYP450 Not inducible Eg. CYP2D6 Genetic polymorphism
Enzyme induction and Inhibition Induction
Inducers: Rifampicin,
Phenytoin, Barbiturate, Carbamazapine Increase synthesis of Micro enzymes→Accelerate the metabolism of substrate Rifampicin X OCP Reduced efficacy Increased toxicity-P.mol and alcoholics Beneficial –Phenobarbitone in newborn jaundice Long time
Inhibition
Inhibitors: Chloramphenicol,
Cipro, E.Mycin Warfarin & E.Mycin→Increased incidence of bleeding Quick
Factors affecting Biotransformation 1. Age-Extremes of age enzymes may be
deficient Eg.Chloramphenicol in premature babies causes Gray baby syndrome. 2. Malnutrition:- metabolism due to enz. proteins. 3.
Liver disease:- metabolism-- … so..dose of drug
4. Genetic: Genetically determined variation in metabolism Slow and fast acetylators-INH SCH
Prodrug Inactive drug Converted to active form by metabolism Improved B.A.-L-Dopa and Dopamine Prolongs duration of action- Fluphenazine Improves taste- Clindamycin palmitate Reduces ADE-Bacampicillin Methenamine release Formaldehyde in acidic urine
Drug Excretion Removal of drug and its metabolites from body Kidney Lungs Bile Feces Sweat Saliva Tears Milk
Excretion-Kidney
Renal excretion
Glomerular Filtration
Tubular secretion
Tubular reabsorption
Glomerular Filtration
Mol.size Depends on Renal blood
flow Plasma protein binding
Tubular secretion-Active Carrier mediated Not affected by PPB Penicillin, Probenecid, Quinine May use same carrier-Nonspecific Probenecid inhibits penicillin secretion
Tubular Reabsorption-Passive Depends on pH and ionization Strongly acidic and alkaline-UnionizedExcreted Weakly acidic-Ionized in alkaline medium-not absorbed. Eg. Alkaline urine and aspirin toxicity Weakly basic-Ionized in acidic urine
Eg. Acidification of urine –NH4cl or VitC-in Amphetamine poisoning
Factors affecting renal excretion
Excretion-Other routes Lungs: Alcohol, G.A, Faeces: Drugs not absorbed and secreted with bile Bile:Excreted in Bile→Reabsorbed from small intestine-This cycle is E.H.circulation
Eg.E.Mycin Skin: As and Hg Saliva: KI, phenytoin. Li Milk:Milk acidic →Alkaline drugs ionized and accumulate. Eg. Tetracycline →ADE in infant
Kinetics of Elimination Fundamental PK Parameters: 1. Vol.of distribution 2. B.A 3. Clearance
THE CLEARANCE OF A DRUG IS THE THEORETICAL VOLUME OF PLASMA FROM WHICH THE DRUG IS COMPLETELY REMOVED IN UNIT TIME Rate of elimination CL= ………………………… Plasma conc.( C)
Elimination: First and Zero Order Kinetics A constant Fraction of the drug in the body is eliminated per unit timeFirst order kinetics: Most drugs A constant Amount of the drug in the body is eliminated per unit timeZero order kinetics: Alcohol To start with First order→As the plasma concn.increases →Zero order←Enzymes get saturated……… Saturation kinetics. Eg.Phenytoin
PLASMA HALF LIFE- t1/2 It is the time required for the plasma conc. of the drug to be reduced to half of its original value
Takes 4-5 halflives to reach steady state concn. 193.5
196.5
198
187.5 175 150
93.5
96.5
98
87.5 100 75 50
100
99
199
Steady state [Plataeu principle]
Elimination First order 100 mg administered[100%] 1 t1/2 50mg 50% 2 t1/2 25mg 75% 3t1/2 12.5 mg 87.5% 4t1/2 6.25.mg 93.75% Take 4-5 halflives for complete elimination of a drug
Clinical Importance of Half Life t½ helps to determine the
duration of action of the drug. To determine the frequency
of drug administration.
To determine the time taken
to achieve the steady state.
Factors Influencing Drug dosage 4-5 half lives for steady state Short half life → repeated admn. Long half life→Takes long time to
reach steady state So loading dose is given for immediate effect Maintainance dose is given to maintain steady state
Therapeutic drug monitoring-TDM Monitoring drug therapy by measuring plasma
conc.of drugs. Indications 1. Drugs with low margin of safetyDigoxin,Lithium 2. To check Pt. compliance. 3. If individual variations are large.- TCA. 4. Potentially toxic drugs used in presence of
renal failure-AMINOGYCOSIDES 5. When Pt. does not respond without reason
Fixed Dose Combinations[FDC] Advantages Better Pt.compliance Synergistic effect
Estrogen+Progesterone Reduced side effect Aspirin+P.mol Prevents microbial resistance INH+Rifampin+PZI Improved efficacy Levodopa+Carbidopa
Disadvantages Inflexible dose ratio Incompatible PK Increased toxicity-with
wrong combinations Ignorance of contents
Eg?
How to prolong duration of action of a drug? Prolong absorption from site of administration Oral- SR tablets, CR. ?Eg Parenteral: Less soluble form, oily prep, adrenaline TTS ?Eg Increase PPB ?Eg Slow down Metabolism ?Eg Reduce Renal Excretion ?Eg
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