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D.K. BADYAL AND A.P. DADHICH

Indian Journal of Pharmacology 2001; 33: 248-259 EDUCATIONAL FORUM

Correspondence: D.K. Badyale-mail:[email protected]

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 Revised: 7.11.2000 Accepted: 10.3.2001

The cytochrome P450(CYP) enzyme family plays a dominant role in the biotransformation of a vastnumber of structurally diverse drugs. There are several factors that influence CYP activity directly or atenzyme 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 isoenzymesof the CYP enzyme system are mainly involved in metabolism of most of the drugs. CYP3A4 isoenzymeis the most predominant isoenzyme in the liver and is involved in the metabolism of approximately 30-40% 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 interactiondata. Based on knowledge of CYP isoenzymes involved in the metabolism of drugs, physicians maybetter anticipate drug interactions. This will enhance the use of rational drug therapy and better drugcombinations.

Cytochrome P450 isoenzymes drug interactionsKEY WORDS

SUMMARY

INTRODUCTION

The cytochrome P450(CYP) enzyme system con-sists 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 un-

dergo CYP mediated oxidative biotransformation is

responsible for the large number of clinically signifi-

cant drug interactions during multiple drug therapy.

Clinical case reports or studies usually provide the

first evidence of interaction between drugs. Severalrecent 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 understand-

ing of the catalytic importance of individual CYP

isoenzymes in particular metabolic pathways.

NOMENCLATURE OF CYP

Nomenclature of CYP enzyme system has been es-tablished by CYP nomenclature committee2. The name

cytochrome P450 is derived from the fact that these

proteins have a heme group and an unusual spec-

trum. These enzymes are characterised by a maxi-

mum 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 fardescribed, 14 exist in all mammals. These 14 families

comprise of 26 mammalian subfamilies2.

Each isoenzyme of CYP is a specific gene product

with characteristic substrate specificity. Isoenzymes

in the same family must have >40% homology in their

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CYP450-DRUG INTERACTIONS

amino acid sequence and members of the same sub-

family 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 isoen-

zymes from the families CYP1, 2 and 3 are involvedin 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 pro-

fessionals 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 inter-actions, mostly as a result of advances in the mo-

lecular biology of the CYP enzyme system. Sev-

eral factors directly or indirectly influence the CYP

activity. Many drug interactions are a result of induc-

tion or inhibition of CYP enzymes.

Enzyme inhibition: Inhibition based drug interac-

tions constitute the major proportion of clinically im-

portant 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 mida-zolam both are substrates for 3A4 isoenzyme so,

there is competition for enzyme sites and metabo-

lism of midazolam is inhibited5. Fluoroquinolones

antimicrobials and azole antifungals, although not

metabolised by CYP3A4 isoenzyme, cause rapid

reversible inhibition of CYP3A4 isoenzyme6,7.

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 istherefore 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 inhibi-

tors of CYP450 enzyme system9,11. Reversible inhi-

bition can be competitive or non-competitive.

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. Thistype of inhibition is known as irreversible or mecha-

nism based or suicide inhibition9,12. Several 17α -

ethinyl substituted steroids e.g. ethinylestradiol,

gestodene and levonorgesterol are reported to cause

mechanism based inhibition9,12.

The extent of competitive or non-competitive inhibi-

tion for reversible inhibition is determined by the rela-

tive binding constants of substrate and inhibitor for

the enzyme and by the inhibitor’s 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 inhibitor’s concentra-tion relative to its Ki value (Ki -inhibition constant

determined in vitro ). Thus, the most potent revers-

ible 3A inhibitors including azole antifungals and first

generation HIV protease inhibitors have Ki value be-

low 1 µM. Inhibition is uncommon for compounds with

Ki value >75-100 µM8. 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 >30-

40% metabolism of a drug and that metabolic path-way is catalysed by a single isoenzyme3. Inhibitor

will decrease the metabolism of substrate and gen-

erally 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 en-

zyme induction are not as common as inhibition

based drug interactions but equally profound and

clinically important. Exposure to environmental pol-lutants as well as large number of lipophilic drugs

can result in induction of CYP enzymes. The most

common mechanism is transcriptional activation lead-

ing to increased synthesis of more CYP enzyme pro-

teins13. If a drug induces its own metabolism, it is

called autoinduction as is the case with carbama-

zepine3. If induction is by other compounds it is called

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foreign induction. Metabolism of the affected drug is

increased leading to decreased intensity and dura-

tion 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 difficultto predict the time course of enzyme induction be-

cause 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 impor-

tant in order to give appropriate multiple drug therapy.

Isoenzymes and drug interactions: The advances

in CYP enzyme system has made it possible to as-

sociate specific enzyme activity with the formation

of a particular metabolite and in some cases to iden-

tify the major isoenzyme responsible for the total

clearance of a drug. Presently we know the individualisoenzymes 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 ac-

count for about 30% of CYP proteins in the liver. High

levels are also present in the small intestinal epithe-

lium and thus makes it a major contributor to presys-

temic elimination of orally administered drugs14. There

is considerable interindividual variability in hepatic and

intestinal CYP3A activity(about 5-10 fold)1. Since 40-50% of drugs used in humans involve 3A mediated

oxidation to some extent, the members of this sub-

family 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 threat-ening 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 T-

type calcium channels, has already been voluntarilywithdrawn 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 contracep-

tives50.

2D6: This isoenzyme represents

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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-uptakeinhibitors(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 polymor-

phism. It is involved in metabolism of a number of

clinically important drugs e.g. omeprazole, diazepam,

antidepressants and antimalarials76. Important inter-

actions are listed in Table 2.

2E1: This isoenzyme is involved in metabolism of

low molecular weight toxins, fluorinated ether vola-

ti le anesthetics and procarcinogens 79. This

isoenzyme is inducible by ethanol and is responsi-

ble in part for metabolism of acetaminophen. The

metabolite of acetaminophen formed is highly reac-

tive 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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Table 2. Drug interactions involving CYP2D6 isoenzymes.

Drugs affected (substrates)

CYP2D6

INHIBITORS

SSRIs: Metoprolol58, tramodol, codeine, ondansetron, tamoxifen59

Fluoxetine Imipramine, desipramine, nortriptyline, haloperidol33,34

Propafenone Propranolol, metoprolol, debrisoquine60

Cimetidine Propranolol, quinidine47

Quinidine Sparteine, debrisoquine61

Terbinafine Nortriptyline62

Amiodarone Flecainide63

CYP1A2

INHIBITORS

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

Fluoxetine Clozapine66, desipramine33,34

Ciprofloxacin Caffeine, theophylline, antipyrine6, tacrolimus46, clozapine66

Grapefruit juice Caffeine44

Cimetidine Theophylline, warfarin47

Verapamil, diltiazem Antipyrine67, theophylline68

Estradiol, levonorgestrel Tacrine69

Omeprazole Theophylline49

INDUCER

Tobacco Theophylline70

CYP2C9

INHIBITORS

Ketoconazole, metronidazole S-warfarin70,73

Fluconazole Phenytoin

9

, S-warfarin

73

Amiodarone, benzbromarone, S-warfarin63,75

Cimetidine, stiripentol Phenytoin3,47

INDUCER

Rifampicin Phenytoin53

CYP2C19

INHIBITORS

Fluvoxamine Imipramine, clomipramine, amitriptyline, diazepam, chloroguanide65

Fluoxetine Imipramine, diazepam3

Omeprazole Diazepam49

Ticlopidine Phenytoin3

Cimetidine Imipramine, benzodiazepines47

Ketoconazole Omeprazole4

INDUCER

Artemisinin Omeprazole77

CYP2E1

INHIBITORS

Disulfiram, isoniazid Chloroxazone78

INDUCER

Ethanol Acetaminophen79

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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 sig-

nificant 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 signifi-

cant alterations in drug interactions.

Age: Activity of CYP enzymes decreases with ad-

vancing age in both the sexes. Metabolism of

antipyrine (metabolised by at least 10 CYP isoen-

zymes, CYP1A2, 2A6, 3A4, 2B6, 2C8, 2C9, 2C18,

2C19, 2D6 and 2E1), lidocaine, diazepam andtheophylline decreases in the elderly80. In vivo activi-

ties of CYP1A2, 3A4, 2C9 and 2D6 have been re-

ported to be low at birth, but maximally increased at

the young adult stage and decreased in old age81.

Gender: Gender based differences in metabolic ac-

tivity of hepatic CYP isoenzymes have been identi-

fied 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 stud-ies. US FDA now encourages inclusion of women in

clinical trials and one of the reasons for this inclu-

sion 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 combina-

tion 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 men-

strual cycle phases was found on the clearance of pa-

racetamol, nitrazepam, salicylates and propranolol83.

Pituitary-liver axis is thought to be an important regula-

tor of CYP expression. Growth hormone deficiency may

lead to down regulation of CYP enzymes84.

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 metabo-

lise drugs. Genetic polymorphism with clinical impli-cations 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 in-

volved in O-demethylation of codeine to morphine.

Hence poor metabolisers exhibit impaired or no an-algesia after codeine administration8,87. Polymor-

phism of 2D6 contributes to the pronounced

interindividual variability observed in the elimination

of important drugs including tricyclic antidepressants,

antipsychotics, mexiletine and several β-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 In-

dian 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 conse-

quences 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 expres-

sion of these isoenzymes may create difficulty in ex-

trapolating 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, study-

ing the effect of a drug interactions in rats may not

be relevant to humans90.

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Hepatic disease: Many studies have shown effect

of liver disease on CYP enzymes. In cirrhotic pa-

tients expression of 1A2, 2E1 and 3A isoenzymes

was decreased. There are reports of alteration of

clearance of drugs metabolised by 3A4 in patients ofcirrhosis9. Activity of 2C19 was reported to be de-

creased in patients of liver disease, but activity of

2D6 was unaltered91. Levels of 2C subfamily have

been reported to be upregulated in patients of he-

patic carcinoma9. Detailed knowledge of these isoen-

zymes 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 ac-

tivity in humans. This inhibition can lead to abnor-

mally high plasma levels and toxicity of drugs that

are metabolised by CYP dependent enzymes andhave low therapeutic ratio. This phenomenon has

been observed with oral anticoagulants in herpes

zoster, theophylline in acute respiratory viral infec-

tion, nifedipine in acute febrile infection and quinine

in malaria92. Tumour necrosis factor and interleukin-

1, 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 in-

duce CYP enzymes in rodents, but in humans these

conditions inhibit CYP enzymes. Obesity has been

reported to increase metabolism of enflurane andsevoflurane 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 en-

zymes72.

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 clini-

cal 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 me-

tabolised by the same isoenzyme is inhibited by in-

hibitors of that isoenzyme. Therefore, these drugs

exhibit the same spectrum of interactions. For ex-

ample phenytoin, warfarin and tolbutamide are me-

tabolised by the same isoenzyme and exhibit a simi-

lar 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 con-

centration, 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) me-

tabolising 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 degreeof inhibition depends only on the dose and elimina-

tion kinetics of the inhibitor and its affinity for the

isoenzyme. However, for slowly reversible or mecha-

nism based inhibition the situation is more complex,

since not only are these factors important but in ad-

dition 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 metabo-lism 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 predic-

tions have been achieved in some situations to esti-

mate the extent of in vivo interactions from in vitro

data. For example, midazolam is almost completely

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metabolised by 3A4 isoenzyme. In vitro interactions

by ketoconazole reveal that Ki is 1µg/L), one could predict from

in vitro model developed by Rowland and Martin thatclearance 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.

CONCLUSION

Drug interactions involving inhibition and induction

of CYP enzymes will undoubtedly continue to be of

scientific interest and clinical importance simply be-

cause of enzyme’s role in metabolism of currently

available and future drugs. Mibefradil, terfenadine andcisapride provide classical examples indicating the

critical importance of CYP enzyme mediated drug

interactions in the development, regulation and ulti-

mate 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. In-

deed an editorial from US FDA suggests that this

type of information will be required for future new

drugs100.

By understanding the unique functions and charac-

teristics of CYP enzymes, physicians may better an-ticipate 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 facili-

tate better selection of drug combinations.

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259

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 phar-

macology 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 year-

2001 (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.

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