drug metabolism

1. DR.VIJAYA KRISHNA
Post graduate student
Department of Pharmacology
GANDHI MEDICAL COLLEGE
Hyderabad, AP.
01 AUG 2012

2. PLAN OF PRESENTATION
• INTRODUCTION
• DEFINITION
• SITES OF BIOTRANSFORMATION
• PHASES OF DRUG METABOLISM
• PHASE-I REACTIONS
• PHASE-II REACTIONS
• ENZYME INDUCTION
• ENZYME INHIBITION
• FACTORS AFFECTING DRUG
METABOLISM
• REFERENCES

3. INTRODUCTION
• 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 bilogical
responses.

4. 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.

5. Why Biotransformation is necessary?:
• To easily eliminate the drug
• To terminate drug action by inactivating it
By changing its physicochemical properties
from: Active /inactive Inactive /active
Lipophilic Hydrophilic
Unionised Ionised
Nonpolar Polar
Plasma protein Free
bound

6. Consequences of Biotransformation
• Active to Inactive:
Phenobarbitone----
Hydroxyphenobarbitone
• Inactive (prodrug) to Active :
L-Dopa ---- Dopamine
Parathion -- Paraoxon
Talampicillin -- Ampicillin

7. • Active to equally active:
Diazepam -- Oxazepam
Amitriptyline -- Nortriptyline
Imipramine -- Des-imipramine
Codeine -- Morphine

8. 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”.

9. 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.
26

10. • First pass effect :Liver-90%, Git-9% and Portal
circulation-1%
• Partially metabolised drugs -
nitroglycerine,propranolol,salbutamol- high
oral dose is required.
• Complete first pass metabolism - isoprenaline,
hydrocortisone, insulin.
• Liver diease- increased bioavailability of drugs.

11. Drugs which undergo first pass effect:
LIVER
• L-DOPA • NICOTINE
BRONCHIAL MUCOSA
INTESTINAL MUCOSA
• ISOSORBIDE
DINITRATE • ALPHA • ISOPRINA
METHYLDOPA LINE
• GLYCERYL
• TESTOSTERONE
TRINITRATE
• PROGESTERONE
• MORPHINE
• CHLORPROMAZI
• PETHIDINE NE
• XYLOCAINE • CLONAZEPAM
• IMIPRAMINE • MIDAZOLAM
• AMITRIPTYLINE • CYCLOSPORINE
• PROPRANOLOL

12.  With in the cell: Endoplasmic reticulum.
smooth ER  microsomal reactions
rough ER  protein synthesis

13. PHASES OF DRUG METABOLISM
PHASE I REACTION PHASE II REACTION
1.Degradative reaction 1.Synthetic reaction
2.Introduction of functional group 2.Conjugates phase 1 metabolite
( -OH, -NH2,-SH,-O -,-COOH) with glucuronic acid,sulfate,acetyl,
methyl groups.
3.Mainly microsomal 3.Microsomal, Mitochondrial &
Cytoplasmic
4.Metabolites formed may be 4.Metabolites formed are usually
smaller, polar/non-polar larger,polar,water soluble & Inactive
Active/Inactive

14. DRUG METABOLIZING ENZYMES
ENZYMES REACTIONS
PHASE 1 “OXYGENASES”
CYP 450 C & O OXIDATION,DEALKYLATION,
FMO N, S & P OXIDATION
EPOXIDE HYDROLASES HYDROLYSIS OF EPOXIDES
PHASE 2 “TRANSFERASES”
SULFOTRANSFERASES(SULT) ADDITION OF SULFATE
UDP-GLUCURONOSYLTRANSFERASES(UGT) ADDITION OF GLUCURONIC ACID
GLUTATHIONE-S-TRANSFERASES(GST) ADDITION OF GLUTATHIONE
N-ACETYL TRANSFERASES(NAT) ADDITION OF ACETYL GROUP
METHYLTRANSFERASES(MT) ADDITION OF METHYL GROUP
OTHER ENZYMES
ALCOHOL DEHYDROGENASES REDUCTION OF ALCOHOLS
ALDEHYDE DEHYDROGENASES REDUCTION OF ALDEHYDES
NADPH-QUINONE OXIDOREDUCTASE(NQO) REDUCTION OF QUINONES

15. MICROSOMAL ENZYMES NON-MICROSOMAL
ENZYMES
1.Smooth endoplasmic reticulum 1.Cytoplasm, mitochondria of
of cells of liver,git,kidney,lungs & hepatic & other tissues(plasma).
skin.
2.Non-specific,inducible. 2.Non-inducible.
3.PHASE-I: most oxidation & 3.PHASE-I: most hydrolysis,
reduction, some hydrolysis. some oxidation & reduction.
4.PHASE-II: only glucuronide 4.PHASE-II: all except
conjugation. glucuronide conjugation.
5.Mainly MFO’s like CYP 450, 5. Include MAO, esterases,
FMO’s, EH, UGT amidases ,transferases ,
conjugases.

16. CYTOCHROME P450
In the Oxido-reductase process 2 microsomal
enzymes play a key role
 Flavo proteins ,NADPH –cyt p-450
oxido-reductase
 Haemoprotein,cyt p-450 serves as terminal
oxidase
• P450 heme reduction is rate limiting step

17. • Microsomal drug oxidations require p450,p450
reductase, NADPH ,O2
• Very low substrate specificity.High lipid solubility
is the only common structural feature of most of
substrates.
• P450 isoforms in liver –cyt1A2 ,2A6 ,2B6 ,2C8,
2C9, 2C18, 2C19, 2D6, 2E1,3A4,3A5

18. Of these isoforms 3A4/5 carry out
biotransformation of about 50% of drugs.
P450 enzymes classified into families denoted by
numbers -1,2,3 and sub families by A,B,C & D
basis of AA sequence and c-DNA . Another
number indicates –specific isoenzymes.

19. NADP+ Drug
CYP CYP Fe+3
e-
R-Ase Drug Drug OH
NADPH
CO CYP Fe+3
CO
CYP-Fe+2 CYP Fe+2 Drug OH
Drug hu
Drug
e-
O2
CYP Fe+2 H2O
O2 Drug
2H+
Electron flow in microsomal drug oxidizing system

20. CYP 450 SUBSTRATES
1A2 Acetaminophen, antipyrine, caffeine, clomipramine, phenacetin,
tamoxifen, theophylline, tacrine, warfarin
2A6 Coumarin, tobacco nitrosamines, nicotine
2B6 Artemisin, bupropion, cyclophosphamide, efavirenz, ifosfamide, ketamine,
mephobarbital, mephenytoin, nevirapine, propofol, selegiline, sertraline
2C8 Taxol, all-trans-retinoic acid
2C9 Celecoxib, flurbiprofen,hexobarbital,ibuprofen, losartan,phenytoin,
tolbutamide, s-warfarin
2C18 Tolbutamide, phenytoin
2C19 Diazepam, s-mephenytoin, naproxen, nirvanol, omeprazole, propranolol.
2D6 Bufurolo, clozapine, debrisoquin, dextromethorphan, encainaide,
fluoxetine, haloperidol, metoprolol, selegiline, tamoxifen, tricyclic
antidepressants.
2E1 Acetaminophen, chlorzoxazone, enflurane, halothane, ethanol
3A4, 3A5 Acetaminophen , cyclosporine, alfentanyl, cocaine, dapsone, diazepam,
erythromycin, lidocaine, lovastatin, methadone ,midazolam, ethinyl
estradiol, mifepristone, terfenadine,tamoxifen,saquinavir.

21.  Microsomal: 1.oxidation – a.CYP dependent
b.CYP independent
2.reduction
3.hydrolysis
 Non-microsomal: 1.oxidation
2.reduction
3.hydrolysis

22. PHASE-I REACTIONS
Reaction Structure Examples
Microsomal
(Cyp 450 dependent):
Oxidation
1.Aromatic R- -------- Phenobarbitone,
hydroxylations Phenytoin,
R- -OH propranolol,
amphetamine,
warfarin, 17α -
ethenyl estradiol
2.Aliphatic RCH2CH3-------> digoxin,ibuprofen,s
hydroxylations RCHOHCH3 ecobarbital,chlorpr
opamide

23. PHASE-I REACTIONS
Reaction Structure Examples
Microsomal
(Cyp 450 dependent):
oxidative Dealkylation
3.N-Dealkylation RN(CH3)2------ Mephobarbitone,
RNHCH3+CH3CHO amitriptyline,
morphine, caffiene,
theophylline
4.O-Dealkylation R-O-CH3------ phenacetin, codiene,
R-OH+HCHO paranitroanisole
5.S-Dealkylation R-SCH3---- R-SH + 6-methylthiopurine
HCHO

24. PHASE-I REACTIONS
Reaction Structure Example
Microsomal
(Cyp 450 dependent):
N-Oxidation
Primary amines RNH2------>RNHOH Aniline,
Chlorpentermine
Secondary amines R1-NH2-R2----> 2-acetyl
R1-NOH-R2 aminofluorene,
acetaminophen
Tertiary amines NR1R2R3----> nicotine,
R1R2R3-N-O methaqualone

25. PHASE-I REACTIONS
Reaction Structure Examples
Microsomal(cyp 450
dependent):
S-Oxidation R1-S-R2---> cimetidine,
R1 -SO-R2 chlorpromazine,
omeprazole, thioridazine
Deamination R-CHNH2-R----> Amphetamine, diazepam
R-COR +NH3
Desulfurisation R1-PS-R2---> Parathion,
R1-PO-R2 thiopental
Dechlorination CCl4---> [CCl3-]---> CHCl3 carbontetrachloride

26. Flavin Monooxygenases
• Also known as zeigler’s enzyme. Neither inducible nor
inhibited.
• six families-FMOs(FMO3 being the most abundant in
liver.)
• FMO3 is able to metabolize nicotine,cimetidine and
ranitidine,clozapine and itopride.
• A genetic deficiency in this enzyme causes the fish-odor
syndrome due to a lack of metabolism of
trimethylamine N-oxide (TMAO) to trimethylamine
(TMA).

27. EPOXIDE HYDROLASE
• Two types: soluble and microsomal
cyp EH
• Drug----------- epoxide-------- inactive
metabolite.
•Highly reactive electrophile
•Binds to DNA,RNA.PROTEINS
•Cell toxicity
• Ex:carbamazepine--carbamazepine-10-11-
epoxide--Trans-dihydrodiol
• Valnoctamide,valproic acid inhibit mEH.

28. PHASE-I REACTIONS
Reaction Structure Examples
Non-microsomal:
Oxidation
Mitochondrial R-CH(OH)CH2NH2- Epinephrine
oxidation R-CH(OH)COOH+NH3
Cytoplasmic C2H5OH-CH3CHO- Alcohol
oxidation CH3COOH
(dehydrogenation)
Plasma oxidative Histamine-Imidazole
processes acetic acid
Xanthine- Uric acid

29. PHASE-I REACTIONS
Reactions Structure Examples
Microsomal
reductions
Nitro Reductions RNO2--RNH2 Chloramphenicol
Azo Reductions RN=NR1- prontosil
RNH2+R1NH2 sulfasalazine
Keto Reduction R-CO-R1- R- cortisone,
CHOH-R1 methadone,
metyrapone
Non-microsomal C(Cl)3CH(OH)2- Chloral hydrate
Reductions: C(Cl)3CH2OH

30. PHASE-I REACTIONS
Reaction Structure Examples
Microsomal Pethidine,
Hydrolysis Lidocaine
Non-Microsomal Procaine---
Hydrolysis PABA
Atropine--
atropic acid
Penicillin-G
Procainamide

31. Non-Enzymatic Biotransformation
• Skeletal muscle relaxants like ATRACURIUM are
metabolised in the plasma spontaneously
through molecular rearrangement without
involvement of any enzyme action.

32. ENZYME INDUCTION
Xenobiotics can influence the extent of drug metabolism
1.by activating transcription
2.by inducing expression of genes

33. Mechanism of enzyme induction:

34. Aryl hydrocarbon Receptor(AHR):
• Induces CYP1A1,1A2,1B1--> activates procarcinogens
• Omeprazole is ligand.
• AHR is a member of super family of transcription
factors (PERIOD,SIMPLEMINDED,HIF).
• AHR has regulatory role in the development of
mammalian CNS – modulating the response to
chemical & oxidative stress.

35. Pregnane X Receptor:
• Structurally similar to steroid hormone receptors.
• Induces CYP3A4 ,Drug Transporters, SULT’s, UGT’s
• LIGANDS: Pregnanolone-16-carbonitrile, Rifampin,
Troleandomycin, Nifidipine, Mevastatin,
troglitazone, Ritonavir, paclitaxel, hyperforin.
• Basis for contraceptive failure.

36. Constitutive Androstane Receptor(CAR):
• Can activate genes even in absence of their ligands.
• LIGANDS: Pesticide 1,4-bisbenzene,
5-pregnane-3,20-dione.
• Induces CYP2B6, 2C9, 3A4, GST, UGT, SULT, Drug &
endobiotic transporters.
• Inverse agonists-androstanol, clotrimazole,meclizine
 PXR & CAR exhibits species difference
Ex: 1.Rifampicin activates human PXR but not that of Rat.
2.Pregnanolone-16-carbonitrile- activates mouse,rat PXR.
3.Meclizine inhibits human CAR but activates mouse CAR.

37. Peroxisome Proliferator Activated Receptor
α(PPARα):
• Highly expressed in liver & kidney.
• LIGAND: 1.fibrates(gemfibrozil, fenofibrate),
2. hypoglycemic drugs(rosiglitazone, pioglitazone)
• Induces 1.enzymes- fatty acids(Arachidonic acid)
2.CYP4A - oxidation of FA & drugs with FA
side chain(leukotiene analogues)
• PPARα does not induce xenobiotic metabolism

38. Enzyme induction by decreased enzyme
degradation(substrate s):
 Troleandomycin, clotrimazole induces CYP3A
 Ethanol induces CYP2E1
 Isosafrole induces CYP1A2

39. ENZYME INHIBITION
• It is basis for several drug interactions. It is a rapid
process.
• Microsomal: 1.Reversible – cimetidine &
ketoconazole binds tightly to cyp450 heme iron and
inhibits metabolism of testosterone.
• Troleandomycin & Erythromycin--> CYP3A4-->
cyp3A4-metabolite complex.
• Proadifen(SKF-525-A)--> bind tightly to heme iron
and partially irreversibly inhibits enzyme.

40. 2. Irreversible(suicidal inhibitors)- intermediate
metabolite bind covalently with P450 apoprotien.
 Ex: spironolactone, ethinyl estradiol, ritonavir
 But Secobarbital inhibits CYP2B1 by binding to heme &
protein moieties.
Non-microsomal:
DRUG ENZYME INHIBITED
ALLOPURINOL XANTHINE OXIDASE
NSAIDS CYCLO-OXYGENASE
THEOPHYLLINE PHOSPHODIESTERASE
DISULFIRAM ALDEHYDE DEHYDROGENASE

41. PHASE-II REACTIONS
GLUCURODINATION(microsomal):
UDP-GA + substrate(Phase-I metabolite)
ALCOHOL & PHENOLIC HYDROXYL groups
CARBOXYL, SULFURYL, CARBONYL moieties
Primary, Secondary & tertiary AMINE linkages.
UGT
Glucuronides(glucopyranosiduronic acids)
Bacterial
glucuronidase
Decojugated substrate
Ex: morphine, acetaminophen, diazepam, N-
hydroxydapsone, digitoxin.

42. • UGT are encoded by 19 genes(9genes on UGT1 locus-
chr.2 & 10genes on UGT2 locus-chr.4)
• UGT1- Glucuronidation of Bilirubin-rate limiting
step.
• UGT2 have greater specificity for endogenous
substances(steroids) glucurodination.

43. PHASE-II REACTIONS
SULFATION(cytosolic):
 Sulfotransferase(SULT) conjugates sulfate- PAPS to
the hydroxyl groups & less frequently to aromatic
and aliphatic amine groups (acetaminophen,
hydroxycoumarins).
 SULT has 13 isoforms.
 SULT play an important role in normal human
homeostasis.
 SULT2B1b –skin-cholesterol-cholesterol sulfate-
regulates keratinocyte differentiation & skin
development.

44. • SULT2A1-fetal adrenal gland -dehydroepiandrosterone
- DHEA sulfate-essential for placental Estrogen
biosynthesis during 2nd half of pregnancy.
• SULT1A3- highly selective for catecholeamines.
• SULT1E1-sulfates endogenous & exogenous steroids.
Ex:-Estrogen(17-estradiol)-estrogen sulfate.
• In humans significant fractions of circulating
catecholamines,estrogens,iodothryronines, DHEA are
exist in sulfate form.

45. PHASE-II REACTIONS
GLUTATHIONE CONJUGATION :
Glutathione(GSH) is a tripeptide of
glycine - glutamic acid - cysteine.
• GSH exists in cell as oxidized form(GS-SH) and
reduced form(GSH).
• GSH:GSSH ratio is critical in maintaining cellular
environment to be in reduced state.
• GSH + Electrophilic compound
GST otherwise react with –O,-N,-S atoms leading to cell damage
Electrophile-Glutathione

46. GLUTATHIONE-S-TRANSFERASE(GST):
• exists in 20 isoforms.
• Cytosolic GST isoforms -7classes - exogenous
drugs & xenobiotics (acetaminophen, ethacrynic
acid, bromobenzene)
• Microsomal GST isoforms-endogenous
leukotrienes & prostaglandins.
• GST play an important role in cellular
detoxification.

47.  Its activity in cancerous tissue has been linked to
development of resistance to chemotherapeutic
agents.
 Anticancer drug----> JNK &P38---->Apoptosis
- Resistance
GST over expression
In tumour cells
 Inhibition of GST activity sensitises tumour cells to
anticancer drugs.
 TLK199(GSH analogue) activated by plasma
esterase to TLK117(GST inhibitor) which potentiates
toxicity of anticancer drugs.

48.  N-Acetylation(cytosol):
• Substrate- Aromatic amine groups & Hydrazine group
such as sulfonamides,isoniazid,clonazepam,
dapsone,etc.
• Co-substrate- acetyl coenzyme A
• Enzyme- N-Acetyl Transferase
 NAT1 & NAT2 – 25 Allelic variants are identified.
 NAT2 mutation – slow & fast acetylation.
 Field of pharmacogenetics has established by the
identification of “The characterisation of an
Acetylator phenotype.”

49.  Methylation(cytosol):
• Substrate: -N, -O, -S atoms containing compounds
• Co-substrate: S-Adenosyl Methionine
• Enzyme: Methyltransferase
Nicotinamide NMT- Serotonin, Tryptophan,
Nicotinamide, Nicotine
N-Methyltransferases -
Phenylethanolamine NMT - Norepinephrine
Histamine NMT - Histamine
Catechol-o-methyltransferase–>Dopamine,Norepinephrine,
Methyldopa, Ecstasy
Phenol-o-methyltransferase –>Tyrosine metabolism
Thiopurine-s-methyltransferase ->Azathioprine,
Thioguanine, 6-MP

50. Amino acid conjugation(mitochondria):
Substrate: aspirin, benzoic acid, nicotinic acid,
deoxycholic acid
Co-substrate: Glycine (or) Glutamine
Enzyme: acyl coenzyme A-glycinetransferase
 Riboside & Riboside phosphates:
 Many purines & pyrimidines form their active
metabolites by forming ribonucleosides and
ribonucleotides.
 Purines and pyrimidines are used as antimetabolites in
cancer chemotherapy.

51. FACTORS AFFECTING DRUG METABOLISM
1. AGE:
Neonates-low microsomal enzymes &
glucuronyl transferase enzyme activity.
ex: chloramphenicol-poor glucuronyl
conjugation- Gray baby syndrome.
Elderly persons- reduced hepatic blood flow.
Ex: propranolol & pethidine

52. FACTORS AFFECTING DRUG METABOLISM
• Sex: male rats metabolise the drugs much faster
than female rats and prepubertal male rats.
male rats sleep for a shorter duration than
female rats after receiving hexobarbital.
In Humans similar sex differences exist for
propranolol, ethanol, estrogens, salicylates.

53. FACTORS AFFECTING DRUG METABOLISM
• Species: Rabbits metabolise Atropine faster than
man as they have high Atropine esterase activity
in the liver and plasma.
• Race: Chinese- high alcohol dehydrogenase
activity & low Aldehyde dehydrogenase activity-
high plasma aldehyde conc.- headache,
palpitation after consuming alcohol.

54. • Diet and environment:
 Low carbohydrate-high protein diet-
metabolism.
 High carbohydrate-low protien diet-
metabolism.
 Starvation – enzyme inhibition.
 Charcoal- broiled foods & cruciferous
vegetables induce CYP1A.
 Grapefruit juice inhibit CYP3A.
 Cigarette smokers metabolise some drugs
more rapidly than non-smokers

55. • Genetic polymorphism: Autosomal recessive traits.
PHASE-I: CYP2D6
DRUG PHENOTYPE EFFECT
debrisoquin PM orthostatic
hypotension
codeine PM dec. analgesic effect.
UM inc. respiratory
depression
tramadol PM inc. seizure risk
nortriptyline PM inc. ADR
UM dec. therapeutic
effect.

56. • PHASE-I: CYP2C19
DRUG PHENOTYPE EFFECT
amitriptyline PM dec. clearance. inc.
ADR
citalopram PM inc. GIT side effects
omeprazole EM inc. therapeutic effect
tamoxifen EM inc. endoxifen. inc.
efficacy. reduces risk of
relapse.
tamoxifen PM dec. endoxifen- dec.
(cyp2d6) therapeutic efficacy.
chlorproguanil EM inc. therapeutic
efficacy.

57. • PHASE-I: CYP2C9
DRUG PHENOTYPE EFFECT
CELECOXIB, PM INC. ADR
DICLOFENAC
WARFARIN PM INC. BLEEDING
RISK
TOLBUTAMIDE PM CARDIOTOXICITY
PHENYTOIN PM NYSTAGMUS,
DIPLOPIA, ATAXIA.

58. • PHASE-II:
Genetic Drug Effect
polymorphism
Pseudocholine esterase Succinylcholine Succinylcholine
apnea
N-Acetyl transferase 2
Slow Acetylation Isoniazid Pheripheral
neuropathy
Sulfonamide Autoimmune
response
Bicyclic Aromatic Bladder cancer
Amines
Fast Acetylation Isoniazid Hepatotoxicity

59. PHASE-II:
Genetic Drug Effect
polymorphism
Thiopurine-s- Azathioprine Thiopurine induced
methyltransferase 6-Mercaptopurine fatal Hematopoietic
(TMPT) Thioguanine toxicity
UDP-Glucuronosyl Bilirubin Crigler-Najjer
transferase syndrome
Gilbert syndrome
Irinotecan Bone marrow toxicity
Life threatening
diarrhoea.
Glutathione S Acetaminophen Acetaminophen
transferase(GST) toxicity- hepatic
necrosis.

60. Drug – Drug interaction during metabolism:
Enzyme inducer Drugs with Metabolism
Phenobarbital & other Barbiturates, choramphenicol, chlorpromazine,
barbiturates cortisol, coumarin anticoagulants, digitoxin,
doxorubicin, estradiol, itraconazole, phenytoin,
quinidine, testosterone, etc.
Phenytoin Cortisol, dexamethasone, digitoxin, itraconazle,
theophylline.
Carbamazepine Carbamazepine, clonazepam, itraconazole
Rifampicin Coumarin anticoagulants, digitoxin, itraconazole,
glucocorticoids, OC Pills, saquinavir.
St.john’s wort Alprazolam, cyclosporine, digoxin, OC Pills,
indinavir, ritonavir, simvastatin, tacrolimus, warfarin
Ritonavir Acutely inhibitor of CYP3A4; Chronicly inducer-
midazolam.

61. Drug – Drug interaction during metabolism:
Enzyme inhibitors Drugs with metabolism
Itraconazole Atorvastatin,cisapride,cyclosporine,
diazepam,digoxin,indinavir, phenytoin,
quinidine, sildenafil, verapamil, warfarin
Isoniazid,chloramphenicol, Dicoumarol, probenecid, tolbutamide
Allopurinol
Disulfiram Ethanol, phenytoin,warfarin
Chlorpromazine Propranolol
Grapefruit juice Alprazolam, atorvastatin, cyclosporine
Ethanol Methnol
Spironolactone Digoxin
Saquinavir Cisapride, ergots, midazolam.
OC Pills Antipyrine.

62. DISEASES:
 Liver diseases - chlordiazepoxide & diazepam
 Cardiac diseases - hepatic blood flow – rate of
metabolism - amitriptyline, desipramine, isoniazid,
labetalol, propanolol, lidocaine,
morphine, pentazocine, verapamil.
 Pulmonary diseases – procainamide, procaine,
antipyrine
 Hypothyroidism - antipyrine, digoxin, methimazole,
beta blockers

63. REFERENCES
• Goodman Gilman - The Pharmacological Basis of
Therapeutics, 12th Edition
• Katzung – Basic & Clinical Pharmacology,
12th Edition
• Sharma – Priciples of Pharmacology,
2nd Edition
• www.google .com