clinical pharmacokintics part 2 dr jayesh vaghela
TRANSCRIPT
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CLINICAL PHARMACOKINETICS -2
Dr. Jayesh Vaghela
104-Jan-14
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Coping with Exposure to Xenobiotics
• Humans come into Contact with foreign chemicals, medicines, or Xenobiotics (substances foreign to body) Through –
- Intentional exposure,
- Accidental exposure,
- Diet.
• Fortunately, a mechanism to rapidly eliminate them is developed
⇓• They do not accumulate in & harm the body
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BIOTRANSFORMATION
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Topics to be discussed
Introduction to Biotransformation
The Phases of Drug Metabolism
Enzyme Induction & Inhibition
Enzymes Metabolising Xenobiotics
Sites of Drug Metabolism
Factors affecting Drug metabolism ( Biotransformation )
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BIOTRANSFORMATION
• Definition :-
“ Biochemical Transformation of
Drugs within the Living Organism,
catalyzed by Enzymes. ”
• Aim :-
Water insoluble → water soluble → easily excreted
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• Advantage :
Critical for survival
• Disadvantage :
Inter-individual variations
Drug-Drug interactions
Toxic & Carcinogenic derivatives
Species differences → limits the use of animal models in new drug
development
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Consequences of Biotransformation
Active Drug Inactive Metabolite :⇒Phenobarbitone → Hydroxyphenobarbitone
( Active Drug ) ( Inactive Metabolite )
Inactive Drug ( Prodrug ) Active Metabolite :⇒L-Dopa → Dopamine
( Prodrug ) ( Active )
Active Drug Equally Active Metabolite⇒Diazepam → Oxazepam
( Active ) ( Active )
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First-Pass Metabolism
• Drug Oral administration G.I.T. Portal circulation ⇒ ⇒ ⇒ ⇒ Liver ( First pass metabolism ) Systemic Circulation⇒• Decreases Bioavailability
• Decreases Therapeutic Response
• Can be bypassed if drug is given –
- Parenterally ( i.v. Xylocaine in Arrhythmias )
Or
- Sublingually ( Isosorbide dinitrate in Angina )
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Drugs Undergoing First-pass Metabolism
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Liver IntestineBronchial Mucosa
• Morphine• Xylocaine• Imipramine• Propranolol• GTN
• L- Dopa• Testosterone• Progesterone• Chlorpromazine
• Nicotine• Isoprenaline
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Site Of Biotransformation
In Cell
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Chemical Pathways Of
Drug Metabolism
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THE DRUG METABOLIZING ENZYMES
(1) Microsomal Enzymes :
• Location : - Smooth Endoplasmic Reticulum of Liver cells,
- Intestinal mucosa, Lungs, Kidney.
• Activity : - Phase 1 reactions
- Phase 2 reaction ( Glucuronyl conjugations )
• Example : - Cytochrome P-450 enzymes
• Metabolize only Lipid-soluble drugs
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(2) Non-Microsomal Enzymes :
• Location : - Cytoplasm,
- Mitochondria of Hepatic cells,
- Plasma.
• Activity : - All Phase 2 reactions ( Except Glucuronyl conjugation )
• Example : - Esterase, - Monoamine Oxidase (MAO),
- Amidase, - Transferase.
(3) Non-enzymatic ( Hofmann ) Elimination :
• Spontaneous Molecular rearrangement, without any enzyme action
• Example - Atracurium
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Phases of Drug Metabolism
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Phase 1 Phase 2
• Introduction of functional groups. -OH, -COOH, -SH ,-NH2
• Alters biological property
• Oxidation/Reduction Reactions
• Enzymes - CYPs, FMO
• Slower reaction rate
• Conjugation of substrate
• Alters Solubility and mol. wt.
• Conjugation / Hydrolysis
• Enzymes - Transferases, EH
• Faster reaction rate
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PHASE-1 REACTIONENZYMES
CYP ( Cytochrome-P450 ) FMO ( Flavin-containing Monooxigenases ) Hydrolytic enzymes
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Cytochrome P-450• Location :- Endoplasmic Reticulum
• Structure :-
Heme Polypeptide chain⇿• Nomenclature :
- CYP → Digit for Family → Letter for Subfamily → Gene number
- e.g. – CYP3A4 ⇒ - Cytochrome P-450
- Family “ 3 ”
- Subfamily “ A ”
- Gene Number “ 4 ”04-Jan-14
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Functions
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Xenobiotic Metabolism Endogenous Steroid Synthesis
• Capacity to metabolize diverse chemicals
⇓
• Sacrifices metabolic turn-over⇓
• T1/2 of drugs 3 – 30 hrs∼ Endogenous compounds = Sec/Min Dopamine, Insulin.
• Substrate specificity
• CYP 19 / Aromatase
⇓• Testosterone → Estrogen
⇓• Can not metabolize xenobiotics
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CYP Family Main Functions
CYP1 • Xenobiotic metabolism
CYP2• Xenobiotic metabolism,• Arachidonic acid metabolism
CYP3 • Xenobiotic and steroid metabolism
CYP7 • Cholesterol 7 -hydroxylationα
CYP11• Cholesterol side-chain cleavage,• Steroid 11 –hydroxylation,β• Aldosterone synthesis
CYP17 • Steroid 17 -hydroxylationαCYP19 • Androgen aromatization
CYP21 • Steroid 21-hydroxylation
CYP24 • Steroid 24-hydroxylation
CYP27 • Steroid 27-hydroxylation04-Jan-14 18
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CYP Enzymes in Metabolism of SomeClinically Important Drugs
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CYP Inducer InhibitorDrugs
metabolized
• 3A4• 3A5
• Barbiturate• Rifampicin
• Erythromycin• Ketoconazole
• Acetaminophen,• Caffeine
• 2D6 -- • Quinidine • Codeine
• 2C8• 2C9
• Barbiturate• Rifampicin
• Fluconazole• Phenytoin• Warfarin
• 2C19• Barbiturate• Rifampicin
--• Diazepam• Omeprazole
• 1A1• 1A2
• Barbiturate• Rifampicin
--• Theophylline• Warfarin
• 2E1 • Alcohol • Disulfiram• General
anaesthetics
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PHASE-1 REACTIONS Oxidation Reduction Hydrolysis
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CYP-dependent Oxydation Reactions(1) Aromatic Hydroxylation:
Phenytoin
Warfarin
Ethinyl estradiol
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(2) Alliphatic Hydroxylation :
Ibuprofen,
Phenobarbital,
Cyclosporin,
Midazolam
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(3) Dealkylation :
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N- dealkylation :
• Morphine• Theophylline
O- dealkylation :
• Codeine
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• Deamination
• Amphetamine • Diazepam
Carbinolamine intermediate
• Dehalogenation
• Halothane
Hepatotoxicity
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•N-Oxidation
• Dapsone
• Clozapine
• Mianserine
•S-Oxidation
• Chlorpromazine
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Cytochrome P-450 Independent reactions
FMO ( Flavin-containing Monooxygenase )
EH ( Epoxide Hydrolase )
Hydrolysis
Reduction
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FMO ( Flavin-containing Monooxygenase )
• Location :- Endoplasmic Reticulum
• 6 families → FMO3 is most important
• Drugs metabolized : - Nicotine, Cimetidine.
• Deficiency causes “ Fish odor syndrome ”
Trimethylamine N-oxide ( TMAO ) → Trimethylamine
• Not induced or inhibited by drug
⇓• No drug-drug interactions
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( EH ) Epoxide Hydrolase
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Carbamazepine
Carbamazepine EPOXIDE
Carbamazepine Di-hydrodiol
Valproate inhibits
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Reduction
• Digoxin
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Antibiotics
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PHASE -2 REACTIONS Glucuronidation
Sulfation Glutathione conjugation
N-acetylation Methylation
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Glucuronidation
• Enzyme : UGT ( UDP-glucuronosyltransferases )
• Co-factor- UDP-glucuronic acid
• Location : - Liver,
- G.I. epithelial cells
• UGT-1 is more important than UGT-2 in drug metabolism
• drugs metabolized : - Morphine,
- Diazepam,
- Digoxin.
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Gilbert’s Syndrome
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Irinotecan
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Sulfation
• Enzyme : - Sulfotransferase
• Co-factor : - Phosphoadenosyl phosphosulfate
• Drugs : - Methyl dopa
- Ethinyl estradiol
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Glutathione Conjugation
• Co-factor : - Glutathione(GSH)
• Enzyme : - GST
(Glutathione-S-Transferase)
• Normally, High ratio of
GSH : GSSG is needed
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N-Acetylation
• Co-factor : - Acetyl CoA
• Enzyme : - N-Acetyl Transferase ( NAT )
• Drugs : - Amide-containing drugs,
e.g. – Isoniazide,
- Sulfonamide,
- Dapsone,
- Clonazepam,
- Benzocaine.
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Methylation
• Cofactor : - S-Adenosylmethionine [ SAM ]
• Enzyme : - Methyltransferase ( MT ) (cytosol)
• Highly substrate specific
• Drugs :
- TPMT--- Azathioprine, 6-MT, thioguanine
- COMT --- dopamine, methyl dopa, nor- epinephrine
- HNMT --- Histamine
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INDUCTION OFDRUG METABOLISM
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PXR – Pregnane X receptor,RXR – Retinoid X ReceptorLigand – Atorvastatin
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Clinical relevance(A) Decreased Plasma Concentration & Therapeutic effect :
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Enzyme inducer Induced enzyme Drugs affected• Phenobarbitone• Phenytoin• Carbamazepine
• CYP3A4• Barbiturates• Vit D• Theophylline
• Rifampicin• Phenobarbitone
• CYP3A4• CYP2C9
• Oral contraceptives• Warfarin
• Smoking• Omeprazole
• CYP1A2• Theophylline• Warfarin
• Ethanol (chronic)• Isoniazide
• CYP2E1• Ethanol itself• General anesthetics
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(B) Drug Toxicity :
Ethanol drinkers
⇓Paracetamol
⇓N-acetyl-P-benzoquinoneimine
⇓Hepatotoxicity
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(C) Therapeutic benefits :
Phenobarbitone given 7 – 14 days before labour
⇓Induces foetal hepatic glucuronyl transferase enzyme
⇓Conjugation of bilirubin to glucuronic acid
⇓Excreted through bile
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ENZYME INHIBITION
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Clinical consequences
(A) Increased plasma concentrations & toxicity :
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Inhibitor Enzyme inhibited Drugs affected
• Cimetidine• Hepatic microsomal
MFO(Mixed Function Oxidase)
• Phenytoin• Warfarin• Theophylline
• Allopurinol • Xanthine oxidase • Azathioprine
• MAO inhibitors • Monoamine oxidase• Morphine• Tricyclic
antidepressants
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(B) Therapeutic benefits :
L- dopa + carbidopa
Disulfiram + Alcohol Alcohol aversion therapy⇒
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Factors affecting drug metabolism Age :
Neonates :
• Low activity of glucuronyl transferase enzyme
⇓
Choramphenicol
⇓
“ Gary baby syndrome ”
Elderly :
Decreased hepatic blood flow
⇓ Propranolol, Pethidine toxicity
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Sex :
Nutrition & diet
Disease :
Genetic variation :
Drug – rug interactions :
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Role of Drug Metabolism in theDrug Development Process
• Before filing the NDA for a new drug,
⇓Enzymes involved in metabolism
Potentiality of metabolites
• long-term carcinogenicity studies in rodents for drugs to be used chronic diseases.
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References
• HL Sharma & KK Sharma, Principles of Pharmacology, 2nd Edition,
Page 37 – 45
• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th
edition, Page 121 – 143
• KD Tripathi, Essentials of Medical Pharmacology, 6th Edition
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