Indian Journal of Pharmacology 2001; 33:

248-259

EDUCATIONAL FORUM

D.K. BADYAL AND A.P. DADHICH

CYTOCHROME P450 AND DRUG INTERACTIONS

D.K. BADYAL, A.P. DADHICH
Department of Pharmacology, Christian Medical College and Hospital, Ludhiana-141008.
Manuscript Received: 31.8.2000
SUMMARY

Revised: 7.11.2000

Accepted: 10.3.2001

The cytochrome P450(CYP) enzyme family plays a dominant role in the biotransformation of a vast
number of structurally diverse drugs. There are several factors that influence CYP activity directly or at
enzyme regulation level. Many drug interactions are a result of inhibition or induction of CYP enzymes.
Inhibition based drug interactions form a major part of clinically significant drug interactions. Six isoenzymes
of the CYP enzyme system are mainly involved in metabolism of most of the drugs. CYP3A4 isoenzyme
is the most predominant isoenzyme in the liver and is involved in the metabolism of approximately 3040% of drugs.
The advances in the identification, isolation and characterisation of different isoenzymes of CYP enzyme
system made it possible to correlate a specific isoenzyme activity with the metabolism of a specific drug.
This will help in prediction of in vivo drug interactions of new drugs based on their in vitro interaction
data. Based on knowledge of CYP isoenzymes involved in the metabolism of drugs, physicians may
better anticipate drug interactions. This will enhance the use of rational drug therapy and better drug
combinations.

KEY WORDS

Cytochrome P450

isoenzymes

drug interactions

INTRODUCTION

NOMENCLATURE OF CYP

The cytochrome P450(CYP) enzyme system consists of a superfamily of hemoproteins that catalyse
the oxidative metabolism of a wide variety of
exogenous chemicals including drugs, carcinogens,
toxins and endogenous compounds such as steroids,
fatty acids and prostaglandins1. The CYP enzyme
family plays an important role in phase-I metabolism
of many drugs. The broad range of drugs that undergo CYP mediated oxidative biotransformation is
responsible for the large number of clinically significant drug interactions during multiple drug therapy.

Nomenclature of CYP enzyme system has been established by CYP nomenclature committee2. The name
cytochrome P450 is derived from the fact that these
proteins have a heme group and an unusual spectrum. These enzymes are characterised by a maximum absorption wavelength of 450 nm in the reduced
state in the presence of carbon monoxide. Naming a
cytochrome P450 gene include root symbol CYP for
humans(Cyp for mouse and Drosophila), an Arabic
numeral denoting the CYP family (e.g. CYP1, CYP2),
letters A, B, C indicating subfamily (e.g. CYP3A,
CYP3C) and another Arabic numeral representing the
individual gene/isoenzyme/isozyme/isoform (e.g.
CYP3A4, CYP3A5)2. Of the 74 gene families so far
described, 14 exist in all mammals. These 14 families
comprise of 26 mammalian subfamilies2.

Clinical case reports or studies usually provide the

first evidence of interaction between drugs. Several
recent studies discuss such drug interactions at the
molecular or enzyme level and therefore constitute
an important link between clinical and experimental
research. Central to this approach is an understanding of the catalytic importance of individual CYP
isoenzymes in particular metabolic pathways.

Correspondence: D.K. Badyal

e-mail:dineshbadyal@rediffmail.com

Each isoenzyme of CYP is a specific gene product

with characteristic substrate specificity. Isoenzymes
in the same family must have >40% homology in their

CYP450-DRUG INTERACTIONS

amino acid sequence and members of the same subfamily must have >55% homology3. In the human liver
there are at least 12 distinct CYP enzymes2. At present
it appears that from about 30 isozymes, only six isoenzymes from the families CYP1, 2 and 3 are involved
in the hepatic metabolism of most of the drugs. These
include CYP1A2, 3A4, 2C9, 2C19, 2D6 and 2E13.
DRUG INTERACTIONS
Metabolic drug interactions between drugs represent
a major concern for the pharmaceutical industry, for
regulatory agencies and clinically for health care professionals and their patients. It has been estimated
that drug interactions may be fourth to sixth leading
cause of death in hospitalised patients in United
States (U.S.)4. During the past few years a revolution
has taken place in our understanding of drug interactions, mostly as a result of advances in the molecular biology of the CYP enzyme system. Several factors directly or indirectly influence the CYP
activity. Many drug interactions are a result of induction or inhibition of CYP enzymes.
Enzyme inhibition: Inhibition based drug interactions constitute the major proportion of clinically important drug interactions. A drug may inhibit the CYP
isoenzyme whether or not it is a substrate for that
isoenzyme. If the two drugs are substrate for the
same CYP isoenzyme then metabolism of one or both
the drugs may be delayed. Erythromycin and midazolam both are substrates for 3A4 isoenzyme so,
there is competition for enzyme sites and metabolism of midazolam is inhibited5. Fluoroquinolones
antimicrobials and azole antifungals, although not
metabolised by CYP3A4 isoenzyme, cause rapid
reversible inhibition of CYP3A4 isoenzyme 6,7.
Macrolide antimicrobials, fluoxetine, lidocaine and
amiodarone cause slowly reversible inhibition of CYP
isoenzymes7,8. These drugs are converted through
multiple CYP dependent steps to nitroso derivatives
that bind with high affinity to the reduced form of CYP
enzymes. Thus CYP enzymes are unavailable for
further oxidation and synthesis of new enzymes is
therefore the only means by which activity can be
restored and this may take several days9. Cimetidine
and macrolide antimicrobials directly form complex
with heme moiety of CYP isoenzyme9,10. Cimetidine,
amiodarone and stiripentol are non-specific inhibitors of CYP450 enzyme system9,11. Reversible inhibition can be competitive or non-competitive.

249

The most selective CYP inhibitors generally fall into

the category known as mechanism based inhibitors.
These drugs are substrates for the target CYP and
are converted to reactive species that covalently bind
to CYP isoenzymes leading to their inactivation. This
type of inhibition is known as irreversible or mechanism based or suicide inhibition9,12. Several 17 ethinyl substituted steroids e.g. ethinylestradiol,
gestodene and levonorgesterol are reported to cause
mechanism based inhibition9,12.
The extent of competitive or non-competitive inhibition for reversible inhibition is determined by the relative binding constants of substrate and inhibitor for
the enzyme and by the inhibitors concentration. The
critical factor for the inhibition index (the ratio of the
intrinsic clearance in presence of inhibitor to that in
the absence of inhibitor), is the inhibitors concentration relative to its Ki value (Ki -inhibition constant
determined in vitro). Thus, the most potent reversible 3A inhibitors including azole antifungals and first
generation HIV protease inhibitors have Ki value below 1 M. Inhibition is uncommon for compounds with
Ki value >75-100 M8. For irreversible inhibition the
critical factor for inhibition is the total amount rather
than the concentration of the inhibitor to which CYP
isozyme is exposed. Lipophilic and large molecular
size drugs are more likely to cause inhibition8. Two
characteristics make a drug susceptible to inhibitory
interactions: one metabolite must account for >3040% metabolism of a drug and that metabolic pathway is catalysed by a single isoenzyme3. Inhibitor
will decrease the metabolism of substrate and generally lead to increased drug effect or toxicity of the
substrate. If the drug is a prodrug then the effect is
decreased. The process of inhibition usually starts
within the first dose of the inhibitor and onset and
offset of inhibition correlates with the half-life of the
drug involved13.
Enzyme induction: Drug interactions involving enzyme induction are not as common as inhibition
based drug interactions but equally profound and
clinically important. Exposure to environmental pollutants as well as large number of lipophilic drugs
can result in induction of CYP enzymes. The most
common mechanism is transcriptional activation leading to increased synthesis of more CYP enzyme proteins13. If a drug induces its own metabolism, it is
called autoinduction as is the case with carbamazepine3. If induction is by other compounds it is called

250

D.K. BADYAL AND A.P. DADHICH

foreign induction. Metabolism of the affected drug is

increased leading to decreased intensity and duration of drug effects. If the drug is a prodrug or it is
metabolised to an active or toxic metabolite then the
effect or toxicity is increased. It is somewhat difficult
to predict the time course of enzyme induction because several factors including the half-life of drug
and enzyme turnover determine the time course of
induction13,14. Understanding these mechanisms of
enzyme induction and inhibition is extremely important in order to give appropriate multiple drug therapy.
Isoenzymes and drug interactions: The advances
in CYP enzyme system has made it possible to associate specific enzyme activity with the formation
of a particular metabolite and in some cases to identify the major isoenzyme responsible for the total
clearance of a drug. Presently we know the individual
isoenzymes involved in the metabolism of large
number of important drugs. Induction or inhibition of
these isoenzymes leads to clinically significant drug
interactions. Individual isoenzymes and their drug
interactions are as follows:
3A Isoenzymes: Members of the 3A subfamily are
the most abundant CYP enzymes in the liver and account for about 30% of CYP proteins in the liver. High
levels are also present in the small intestinal epithelium and thus makes it a major contributor to presystemic elimination of orally administered drugs14. There
is considerable interindividual variability in hepatic and
intestinal CYP3A activity(about 5-10 fold)1. Since 4050% of drugs used in humans involve 3A mediated
oxidation to some extent, the members of this subfamily are involved in many clinically important drug
interactions8. 3A4 is the major isoenzyme in the liver.
3A5 is present in the kidneys. Inducers of 3A4 usually
do not upregulate 3A5 activity5,8.
Important drug interactions of 3A4 are listed in
Table 1. Noteworthy is high concentration of
terfenadine, astemizole and cisapride when these
drugs are taken concomitantly with azole antifungals
or macrolide antibiotics or fluoxetine or fluvoxamine.
High concentration of these drugs lead to life threatening cardiac arrhythmias like torsades de pointes
and ventricular fibrillation16,18,27. Terfenadine has been
withdrawn in USA and the European Union 32.
Fexofenadine, the active metabolite of terfenadine,
is now marketed as a noncardiotoxic alternative to
terfenadine. U.S. Food and Drug Administration(FDA)

is currently considering to contraindicate the use of

selective serotonin reuptake inhibitors(SSRI) with the
non-sedating antihistamines41. Mibefradil, a newer
calcium channel blocker, that preferentially blocks Ttype calcium channels, has already been voluntarily
withdrawn from the market because of large number
of drug interactions42.
Grapefruit juice(GFJ) is often taken at breakfast in
the western countries when drugs are also often
taken. GFJ contains bioflavonoids mainly naringin
and furacoumarin which cause mechanism based
inhibition of presystemic elimination of a number of
drugs and increase their bioavailability43-45.
An important interaction involving induction of 3A is
the reduction in efficacy of oral contraceptives by
rifampicin and rifabutin, because of an induction of
the 3A mediated metabolism of estradiol and
norethisterone, the components of oral contraceptives50.
2D6: This isoenzyme represents <5% of total CYP
proteins57. It has aroused great interest because of
its large number of substrates(30-50 drugs) and its
genetic polymorphism3. It is also called debrisoquine
hydroxylase after the drug that led to the discovery of
i t s genetic deficiency. Many psychotropic,
antiarrhythmic and -adrenergic receptor blocker drugs
are substrates as well as inhibitors of 2D69,59. Important drug interactions of 2D6 are listed in Table 2.
IA2: This is the only isoenzyme affected by tobacco.
Cigarette smoking may lead to threefold increase in
1A2 activity. Theophylline is metabolised in part by
1A2, which explains why smokers require higher
doses of theophylline than non-smokers70. Alcohol
inhibits metabolism of caffeine, a substrate of 1A2.
Alcohol has been reported to mask the 1A2 inducing
potential of smoking71. Exposure to polyaromatic
hydrocarbons found in charbroiled food can also induce this isoenzyme. This isoenzyme also causes
metabolic activation of procarcinogens to carcinogens e.g. aromatic and heterocyclic amines72. Interactions involving 1A2 are shown in Table 2.
2C9: S-warfarin and phenytoin, both involved in large
number of drug interactions, are metabolised mainly
by 2C93,73. St Johns wart a herbal antidepressant has
been reported to decrease levels of warfarin by induction of 2C974. Interactions of 2C9 are shown in Table 2.

CYP450-DRUG INTERACTIONS

251

Table 1. Drug interactions involving CYP3A4 isoenzymes.

Drugs affected (substrates)

INHIBITORS
Azole antifungals:

Midazolam8, tacrolimus15, terfenadine16, triazolam17

Itraconazole

Cisapride18, quinidine19, astemizole20, methylprednisolone21, buspirone22,

felodipine23, vincristine24, atorvastatin25

Ketoconazole

Terfenadine16, astemizole20, cyclosporine9, triazolam, alprazolam26

Fluconazole

Terfenadine16, triazolam17

Macrolide antimicrobials:

Tacrolimus15, astemizole20

Erythromycin

Carbamazepine3, triazolam17, buspirone22, terfenadine27, simvastatin28

Clarithromycin

Pimozide29, cyclosporin30, midazolam31

Selective serotonin re-uptake

inhibitors(SSRIs):

Midazolam4, cisapride32

Fluoxetine

Diazepam, alprazolam33, midazolam8, terfenadine34,35

Paroxetine

Alprazolam33

Calcium channel blockers:

Tacrolimus15

Verapamil

Simvastatin28, carbamazepine, cyclosporine36

Diltiazem

Triazolam17, carbamazepine, cyclosporine36, quinidine, simvastatin37,

midazolam, alfentanil38

Nifedipine

Midazolam4

Protease inhibitors

Terfenadine, astemizole, cisapride39, midazolam40

Grapefruit juice

Felodipine, nifedipine, nimodipine, nitrendipine, terfenadine, cyclosporin, midazolam,

carbamazepine, simvastatin43, verapamil, prednisolone, ethinylestradiol44, artemether45

Ciprofloxacin

Tacrolimus46

Cimetidine

Carbamazepine3, quinidine19, cyclosporine, calcium channel blockers, benzodiazepines47

Propofol

Midazolam48

Nafimidone, omeprazole

Carbamazepine3,49

INDUCERS
Rifampicin

Protease inhibitors9, diazepam, triazolam, midazolam17, estradiol, norgesterol50, lidocaine51,

zopiclone, zolpidem52, ondansetron53

Rifabutin

Protease inhibitors9, estradiol, norgesterol50

Carbamazepine

Protease inhibitors9, midazolam17, itraconazole54, vincristine55

Phenytoin, Phenobarbitone

Midazolam17, vincristine55, carbamazepine56

2C19: This isoenzyme also exhibits genetic polymorphism. It is involved in metabolism of a number of
clinically important drugs e.g. omeprazole, diazepam,
antidepressants and antimalarials76. Important interactions are listed in Table 2.
2E1: This isoenzyme is involved in metabolism of
low molecular weight toxins, fluorinated ether vola-

tile anesthetics and procarcinogens 79. This

isoenzyme is inducible by ethanol and is responsible in part for metabolism of acetaminophen. The
metabolite of acetaminophen formed is highly reactive and hepatotoxic. Alcohol dependant patients may
be at increased risk of acetaminophen hepatotoxicity
because of induction of 2E1 by alcohol79. Isoniazid
has biphasic effect on 2E1 activity, a direct inhibitory

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D.K. BADYAL AND A.P. DADHICH

Table 2. Drug interactions involving CYP2D6 isoenzymes.

Drugs affected (substrates)
CYP2D6
INHIBITORS
SSRIs:

Metoprolol58, tramodol, codeine, ondansetron, tamoxifen59

Fluoxetine
Propafenone

Imipramine, desipramine, nortriptyline, haloperidol33,34

Propranolol, metoprolol, debrisoquine60

Cimetidine

Propranolol, quinidine47

Quinidine
Terbinafine

Sparteine, debrisoquine61
Nortriptyline62

Amiodarone
CYP1A2

Flecainide63

INHIBITORS
Fluvoxamine
Fluoxetine

Melatonon64, tacrine, imipramine, clomipramine, theophylline, caffeine, clozapine65

Clozapine66, desipramine33,34

Ciprofloxacin
Grapefruit juice

Caffeine, theophylline, antipyrine6, tacrolimus46, clozapine66

Caffeine44

Cimetidine

Theophylline, warfarin47

Verapamil, diltiazem
Estradiol, levonorgestrel

Antipyrine67, theophylline68
Tacrine69

Omeprazole
INDUCER

Theophylline49

Tobacco

Theophylline70

CYP2C9
INHIBITORS
Ketoconazole, metronidazole
Fluconazole

S-warfarin70,73
Phenytoin9, S-warfarin73

Amiodarone, benzbromarone,

S-warfarin63,75

Cimetidine, stiripentol
INDUCER

Phenytoin3,47

Rifampicin
CYP2C19

Phenytoin53

INHIBITORS
Fluvoxamine
Fluoxetine

Imipramine, clomipramine, amitriptyline, diazepam, chloroguanide65

Imipramine, diazepam3

Omeprazole
Ticlopidine

Diazepam49
Phenytoin3

Cimetidine

Imipramine, benzodiazepines47

Ketoconazole
INDUCER

Omeprazole4

Artemisinin
CYP2E1

Omeprazole77

INHIBITORS
Disulfiram, isoniazid
INDUCER

Chloroxazone78

Ethanol

Acetaminophen79

CYP450-DRUG INTERACTIONS

effect immediately after its administration followed by

an inducing effect because of CYP protein
stabilisation1. Important interactions of 2E1 are listed
in Table 2.
Knowledge of substrates, inhibitors and inducers of
CYP isoenzymes assists in predicting clinically significant drug interactions.
Other factors affecting the expression of CYP
proteins: Apart from drugs, the following factors may
affect expression of CYP proteins and lead to significant alterations in drug interactions.
Age: Activity of CYP enzymes decreases with advancing age in both the sexes. Metabolism of
antipyrine (metabolised by at least 10 CYP isoenzymes, CYP1A2, 2A6, 3A4, 2B6, 2C8, 2C9, 2C18,
2C19, 2D6 and 2E1), lidocaine, diazepam and
theophylline decreases in the elderly80. In vivo activities of CYP1A2, 3A4, 2C9 and 2D6 have been reported to be low at birth, but maximally increased at
the young adult stage and decreased in old age81.
Gender: Gender based differences in metabolic activity of hepatic CYP isoenzymes have been identified in humans. Women exhibit higher baseline 3A4
activity than men and therefore a greater extent of
interactions on average81. Clearance of diazepam and
prednisolone is more in women, but clearance of
some drugs like propranolol are more in men81. Male
subjects typically have been used in most drug studies. US FDA now encourages inclusion of women in
clinical trials and one of the reasons for this inclusion is variation in drug metabolising enzymes82.
Hormones: Testosterone deficiency decreases CYP
activity. This may the reason for decreased activity of
CYP enzymes in the elderly81. Estrogen has been found
to decrease oxidation of some drugs e.g. imipramine.
Oral contraceptives(estrogen/progesterone combination preparations) were reported to decrease clearance
of diazepam and chlordiazepoxide83. Menstrual cycle
phases have variable effect on CYP activity.
Theophylline clearance was found to be decreased in
luteal phase81. Increased metabolism of antipyrine was
reported near the time of ovulation83. No effect of menstrual cycle phases was found on the clearance of paracetamol, nitrazepam, salicylates and propranolol83.
Pituitary-liver axis is thought to be an important regulator of CYP expression. Growth hormone deficiency may
lead to down regulation of CYP enzymes84.

253

Genetic polymorphism: As each isoenzyme is a

specific gene product, genetic variations influence
the expression of isoenzymes in different individuals
and hence the capacity of the individual to metabolise drugs. Genetic polymorphism with clinical implications has been described for 2D6, 2C19, 2C9 and
1A29,85,86. These isoenzymes exhibit polymorphism
with number of allelic variants, the frequency of which
often varies between different populations.
About 5-10% of Caucasians and 1% of Asians are
poor metabolisers of drugs metabolised by 2D69. The
frequency of poor metabolisers in Indian population
is about 2-4.8%87. Poor metabolisers are more prone
to adverse drug reactions because metabolism is
decreased and blood levels are high. CYP2D6 is involved in O-demethylation of codeine to morphine.
Hence poor metabolisers exhibit impaired or no analgesia after codeine administration 8,87. Polymorphism of 2D6 contributes to the pronounced
interindividual variability observed in the elimination
of important drugs including tricyclic antidepressants,
antipsychotics, mexiletine and several -adrenergic
receptor blockers59. About 5% of whites and 20% of
Asians are poor metabolisers of drugs metabolised
by 2C199. The frequency of poor metabolisers in Indian population is about 11-20%76. The Chinese are
poor metabolisers of 2C19 and are more prone to
sedative effect of diazepam and they are prescribed
lower doses of diazepam. In case of 1A2 only 3-4%
of white population is poor metaboliser80.
An area of growing interest is that relating to consequences of inhibitory interactions of drugs subjected
to isoenzyme polymorphism. Dual drug therapy for
eradication of helicobacter pylori is more beneficial
in poor metabolisers of 2C19 than extensive
metabolisers. This is because of decreased
metabolisn of omeprazole in poor metabolisers and
inhibition of omeprazole metabolism by
clarithromycin89. Poor metabolisers of phenytoin (less
2C19 activity) will require lower doses of phenytoin
and chances of interaction between phenytoin and
felbamate will be less3. Species variation in expression of these isoenzymes may create difficulty in extrapolating results of drug interactions from animals
to humans. For example, in humans there is only one
active 2DCYP isoenzyme, the 2D6 isoenzyme. In rats
there are 5 or 6 different 2D isoenzymes. So, studying the effect of a drug interactions in rats may not
be relevant to humans90.

254

D.K. BADYAL AND A.P. DADHICH

Hepatic disease: Many studies have shown effect

of liver disease on CYP enzymes. In cirrhotic patients expression of 1A2, 2E1 and 3A isoenzymes
was decreased. There are reports of alteration of
clearance of drugs metabolised by 3A4 in patients of
cirrhosis9. Activity of 2C19 was reported to be decreased in patients of liver disease, but activity of
2D6 was unaltered91. Levels of 2C subfamily have
been reported to be upregulated in patients of hepatic carcinoma9. Detailed knowledge of these isoenzymes affected in disease states would be used to
enhance the design of rational drug therapy.
Inflammation: Acute phase response inflammatory
mediators have been reported to suppress CYP activity in humans. This inhibition can lead to abnormally high plasma levels and toxicity of drugs that
are metabolised by CYP dependent enzymes and
have low therapeutic ratio. This phenomenon has
been observed with oral anticoagulants in herpes
zoster, theophylline in acute respiratory viral infection, nifedipine in acute febrile infection and quinine
in malaria92. Tumour necrosis factor and interleukin1, two major inflammatory cytokines probably play a
role. These factors have been reported to inhibit CYP
enzymes in rats and mice92.
Nutrition: Starvation and obesity are known to induce CYP enzymes in rodents, but in humans these
conditions inhibit CYP enzymes. Obesity has been
reported to increase metabolism of enflurane and
sevoflurane in humans93.
Environmental factors: Cigarette smoking is known
to induce CYP enzymes. Smoking has been found
to increase clearance of phenacetin and
theophylline70. Charbroiled food can induce CYP enzymes72.
Pregnancy: Pregnancy may induce CYP enzymes.
Increased metabolism of metoprolol was found in
pregnant women due to induction of 2D6
isoenzyme94.
Keeping in view the above factors the dose of the
substrate for affected isoenzymes must be altered.
PREDICTION OF INTERACTIONS
The prediction of inhibition based interactions has
been possible for new drug candidates as a result of
identification of CYP isoenzymes and an increased

awareness of their in vitro and in vivo behaviour. For

any new drug the spectrum of drug interactions can
be predicted even before the drug reaches the clinical phase of development96,99. These predictions are
based on the following principles:
If the drug of interest is substrate: In vivo and in
vitro inhibition is isoenzymes specific and substrate
independent. Metabolism of all drugs that are metabolised by the same isoenzyme is inhibited by inhibitors of that isoenzyme. Therefore, these drugs
exhibit the same spectrum of interactions. For example phenytoin, warfarin and tolbutamide are metabolised by the same isoenzyme and exhibit a similar spectrum of interactions, even though these drugs
are unrelated chemically, pharmacologically and
therapeutically3,73.
If the drug of interest is inhibitor: The potential for
any new drug to inhibit the various isoenzymes of
CYP can be assessed in vitro using probes. If the
new drug inhibits one isoenzyme at therapeutic concentration, we can predict that it will interact with any
substrate of that isoenzyme. It is important to note
that a drug may inhibit an isoenzyme whether or not
it is a substrate of that isoenzyme. For example,
fluconazole inhibits the major isoenzyme (2C9) metabolising phenytoin, but it is not a substrate for that
isoenzyme. In fact, its major route of elimination is
renal8. In principle, the situation for rapidly reversible
inhibition is relatively straightforward i.e. the degree
of inhibition depends only on the dose and elimination kinetics of the inhibitor and its affinity for the
isoenzyme. However, for slowly reversible or mechanism based inhibition the situation is more complex,
since not only are these factors important but in addition the rate of enzyme complexation/inactivation
and synthesis as well as the degradation of the
holoenzyme are determinants8. Accordingly in vivo
prediction of these types of inhibition is difficult. A
critical aspect of any a priori prediction concerns the
accuracy of the Ki determined in vitro. Experimental
conditions such as incubation time, concentration of
drug at the enzyme site and non-hepatic metabolism limit the ability of in vitro system to predict in
vivo interactions8,99. Although most of the predictions
are still at the qualitative level, quantitative predictions have been achieved in some situations to estimate the extent of in vivo interactions from in vitro
data. For example, midazolam is almost completely

CYP450-DRUG INTERACTIONS

metabolised by 3A4 isoenzyme. In vitro interactions

by ketoconazole reveal that Ki is <0.1 M/L. Knowing this Ki value and achievable plasma concentration of ketoconazole(>1 g/L), one could predict from
in vitro model developed by Rowland and Martin that
clearance of midazolam after oral administration of
ketoconazole is decreased by 95%. This prediction
was confirmed by a clinical study in which midazolam
clearance was decreased by 94% after ketoconazole
administration4 .

Feyereisen R, Waxman DJ et al. P450 superfamily: update on new sequence, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996;6:1-42.
3.

Levy RH. Cytochrome P450 isozymes and antiepileptic

drug interactions. Epilepsia 1995;36:8S-S13.

4.

Yuan R, Parmelee T, Balian JD, Upoor RS, Ajayi F, Burnett

A et al. In vitro interaction studies: experience of the food
and drug administration. Clin Pharmacol Ther 1999;66:915.

5.

Olkkola KT, Aranko K, Luurila H, Hiller A, Saarnivaara L,

Himberg JJ et al. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacokinet
1993;53:298-305.

6.

Janknegt R. Drug interactions with quinolones. J Antimicro

Chemo 1990;26:7-29.

7.

Von Moltke LL, Greenblatt DJ, Schider J, Duan SX, Wright

CE, Harmatz JS et al. Midazolam hydroxylation by human
liver misrosomes in vitro: inhibition by fluoxetine,
norfluoxetine and azole antifungals. J Clin Pharmacol
1996;52:231-8.

8.

Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving CYP3A. Ann Rev Pharmacol Toxicol
1998;38:389-430.

9.

Murray M. P450 enzymes: inhibition mechanisms, genetic

regulation and effect of liver disease. Clin Pharmacokinet
1992;23:132-46.

CONCLUSION
Drug interactions involving inhibition and induction
of CYP enzymes will undoubtedly continue to be of
scientific interest and clinical importance simply because of enzymes role in metabolism of currently
available and future drugs. Mibefradil, terfenadine and
cisapride provide classical examples indicating the
critical importance of CYP enzyme mediated drug
interactions in the development, regulation and ultimate economic success of drugs33,38. Our knowledge
of the isoenzymes involved in metabolism of drugs
will allow a prediction of interactions of these drugs
with new drugs, to be developed in the future. Indeed an editorial from US FDA suggests that this
type of information will be required for future new
drugs100.
By understanding the unique functions and characteristics of CYP enzymes, physicians may better anticipate and manage drug interactions. This practice
will increase in future and will result in the formation
of a rational information base that would indicate drug
combinations to be avoided. For example inhibitors
or inducers of 3A4 isoenzyme would not be given
along with substrates of 3A4 and instead will receive
alternative drugs that are not inhibitors or inducers
of 3A4. This will improve rational drug use and facilitate better selection of drug combinations.

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REGIONAL RESEARCH LABORATORY, JAMMU

Dr. I.C. CHOPRA MEMORIAL AWARD
FOR THE YEAR - 2001
To commemorate the contributions of Dr. I.C. Chopra, Ex Head (1957-1964), Regional
Research Laboratory, Jammu, an annual "Dr. I.C. Chopra Memorial Award" in the area of pharmacology was instituted last year through the kind generosity of Mrs. M. Chopra W/o Late
Dr. I.C. Chopra.
Applications on the prescribed format are invited for Dr. I.C. Chopra Memorial Award for the year2001 (Cash award of Rs.10,000 along with a medal and citation) from the Indian Nationals with
proven contribution in the field of Drug development & General / Biochemical Pharmacology.

Please contact for further information:

The Director,
Regional Research Laboratory,
Canal Road, Jammu Tawi-180 001.
Last date for receiving filled in applications in all respects is September 30, 2001.