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12 Effect of Food, Alcohol Consumption, and Smoking on Drug Disposition

12 Effect of Food, Alcohol Consumption, and Smoking on Drug Disposition

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14.12 Effect of Food, Alcohol Consumption, and Smoking on Drug Disposition

amount of orange juice showed no effect [9]. Subsequent investigations demonstrated that the pharmacokinetics of approximately 40 other drugs are also

affected by intake of grapefruit juice [10]. The main mechanism for enhanced

bioavailability of drugs after intake of grapefruit juice is as follows:

Furanocoumarins found in grapefruit juice inhibit CYP3A4 in the small

intestine, thus inhibiting the metabolism of drugs in the small intestine

and increasing the concentration of available drugs. Grapefruit juice does

not inhibit liver CYP3A4. Therefore, if the drug is injected, no change in

pharmacokinetics is observed.

Grapefruit juice also inhibits P-glycoprotein, thus inhibiting its drug

efflux metabolism, which indirectly increases the bioavailability of a drug

that is a substrate for P-glycoprotein.

Common drugs that interact with grapefruit juice include alprazolam,

carbamazepine, cyclosporine, erythromycin, methadone, quinidine,

simvastatin, and tacrolimus.

There are two types of interactions between alcohol and a drug: pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions occur when

alcohol interferes with the hepatic metabolism of a drug. Pharmacodynamic

interactions occur when alcohol enhances the effect of a drug, particularly in

the central nervous system. In this type of interaction, alcohol alters the effect

of a drug without changing its concentration in the blood. The package insert

of many antibiotics and other drugs states that the medication should not be

taken with alcohol due to drugÀalcohol interactions. Fatal toxicity can occur

from alcohol and drug overdoses due to pharmacodynamic interactions. In a

Finnish study, it was found that median amitriptyline and propoxyphene

concentrations were lower in alcohol-related fatal cases compared to cases

where no alcohol was involved. The authors concluded that when alcohol

was present, a relatively small overdose of a drug could cause fatality [11].

Approximately 4,800 compounds are found in tobacco smoke, including nicotine and carcinogenic compounds such as polycyclic aromatic hydrocarbons

(PAHs) and N-nitroso amines. PAHs induce CYP1A1, CYP1A2, and possibly

CYP2E1, and may also induce Phase II metabolism. Key points regarding the

effect of smoking on drug metabolism include:

Cigarette smoke (not nicotine) is responsible for the alteration of drug


Increased theophylline metabolism in smokers due to induction of

CYP1A2 is well documented.

In one study, the half-life of theophylline was reduced by almost two-fold in

smokers compared to non-smokers [12]. Significant reductions in drug concentrations with smoking have been reported for caffeine, chlorpromazine,

clozapine, flecainide, fluvoxamine, haloperidol, mexiletine, olanzapine,



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propranolol, and tacrine due to increased metabolism of these drugs.

Smokers may therefore require higher doses than non-smokers in order to

achieve pharmacological responses [13]. Warfarin disposition in smokers is

also different than in non-smokers. One case report described an increase in

International Normalization Ratio (INR) to 3.7 from a baseline of 2.7 to 2.8

in an 80-year-old man when he stopped smoking. Subsequently, his warfarin

dose was reduced by 14% [14].



For a meaningful interpretation of a serum drug concentration, the time of

specimen collection should be noted along with the time and date of the

last dose and route of administration of the drug. This is particularly

important for aminoglycosides because, without knowing the time of specimen collection, the serum drug concentration cannot be interpreted. The

information needed for proper interpretation of drug levels for the purpose

of therapeutic drug monitoring is listed in Table 14.2. Reference ranges of

various therapeutic drugs are provided with the result. Therapeutic ranges

of common drugs are given in Table 14.3. However, therapeutic ranges may

vary slightly between different laboratories due to variations in the patient


Usually therapeutic drug monitoring should be ordered after a drug reaches

its steady state. It typically takes at least five half-lives after initiation of a

drug therapy to reach steady state. For example, the half-life of digoxin is

1.6 days, and the steady state of digoxin is reached after 7 days of therapy.

However, for a drug with a shorter half-life than digoxin, for example, valproic acid (half-life 11À17 hours), it takes only three days to reach the steady

state. Pre-analytical errors can contribute significantly to an erroneous result

for therapeutic drug monitoring. For example, collecting a specimen in a

serum separator tube can affect the concentrations of a few therapeutic drugs

(phenytoin, valproic acid, and lidocaine).


Phenytoin, phenobarbital, primidone, ethosuximide, valproic acid, and carbamazepine are considered as conventional anticonvulsant drugs. All of

these antiepileptic drugs have a narrow therapeutic range requiring therapeutic drug monitoring. Phenytoin, carbamazepine, and valproic acid are

also strongly bound to serum proteins. Therefore, for a selected patient

population, monitoring free phenytoin, free valproic acid, and, to a lesser

14.14 Monitoring of Anticonvulsants

Table 14.2 Information Required for Interpretation of Therapeutic

Drug Monitoring Results

Patient-related Information Required on the Request

Name of the patient

Hospital identification number


Gender (pregnant female?)


Other Essential Information

Time of last dosage

Type of and number of specimen (serum, whole blood urine, saliva, other body fluid)

Identification of peak versus trough specimen (for aminoglycosides and vancomycin only)

Special request (such as free phenytoin)

Essential Information Needed for Interpretation of Result

Dosage regimen

Other drugs the patient is receiving

Concentration of the drug

Pharmacokinetic parameters of the drug

Is the patient critically ill or suffering from hepatic, cardiovascular or renal disease?

Albumin level, creatinine clearance

extent, free carbamazepine, is clinically useful. However, free phenobarbital

monitoring is not required because this drug is only moderately bound to

serum protein. Free phenytoin is the most commonly ordered free drug

monitoring request in the hospital where this author works. Monitoring

free phenytoin (and also free valproic acid) is recommended in the following patients:

Uremic patients.

Patients with liver disease.

Pediatric population (small children often show impaired protein

binding or altered disposition).

Pregnant women.

Critically ill patients, elderly patients, and patients with


In addition, monitoring free phenytoin concentration is useful in patients

where a drugÀdrug interaction is suspected. Several strongly protein-bound

drugs such as valproic acid, non-steroidal anti-inflammatory drugs (aspirin,



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Table 14.3 Therapeutic Level of Commonly Monitored Drugs

Drug Class/Drug

Recommended Therapeutic Range (Trough)






Valproic acid



10À20 μg/mL

4À12 μg/mL

15À40 μg/mL

5À12 μg/mL

50À100 μg/mL

10À75 ng/mL

3À14 μg/mL

Cardioactive Drugs



N-Acetyl Procainamide



0.8À1.8 ng/mL

4À10 μg/mL

4À8 μg/mL

2À5 μg/mL

1.5À5 μg/mL




10À20 μg/mL

5À15 μg/mL


Amitriptyline 1 nortriptyline


Doxepin 1 nordoxepin

Imipramine 1 desipramine


120À250 ng/mL

50À150 ng/mL

150À250 ng/mL

150À250 ng/mL

0.8À1.2 mEq/L






Mycophenolic acid

100À400 ng/mL

5À15 ng/mL

4À20 ng/mL

3À8 ng/mL

1À3.5 μg/mL



Varies with therapy type




20À35 μg/mL, Peak

4À8 μg/mL, Trough

5À10 μg/mL, Peak

,2 μg/mL, Trough


14.14 Monitoring of Anticonvulsants

Table 14.3 Therapeutic Level of Commonly Monitored Drugs


Drug Class/Drug

Recommended Therapeutic Range (Trough)


5À10 μg/mL, Peak

,2 μg/mL, Trough

20À40 μg/mL, Peak

5À15 μg/mL, Trough


Therapeutic ranges are based on published literature, including books and adaptations from reputed

national reference laboratories (e.g. Mayo Medical Laboratories and ARUP laboratories). Please note

that therapeutic ranges can vary widely among different patient populations and that each institute

should establish its own guidelines. These values are provided as examples only.

*Monitored in whole blood instead of serum or plasma.

ibuprofen, naproxen, tolmetin, etc.), and certain antibiotics (ceftriaxone, nafcillin, oxacillin, etc.) can displace phenytoin from the protein-binding site,

thus causing an elevated free phenytoin level.


A 72-year-old man with coronary artery disease was hospitalized for coronary revascularization. On the 5th day after surgery, new onsets of focal seizure led to initiation of phenytoin

therapy. Because the seizures were not controlled completely

by phenytoin, phenobarbital was also introduced. His biochemical tests were normal. The patient suffered a respiratory

arrest on the tenth hospital day, was intubated, and his condition improved. On the 25th hospital day (9 days after cessation

of seizure activity, and 2 days after discontinuation of phenobarbital) the patient was still receiving phenytoin and showed

lethargy accompanied by nystagmus (indicating phenytoin

toxicity), although his total phenytoin was within therapeutic

range (19.6 μg/mL; therapeutic range: 10À20 μg/mL). At that

time, his free phenytoin level was determined and was found

to be toxic (4.4 μg/mL; therapeutic: 1À2 μg/mL). Although free

phenytoin represents 10% of total phenytoin level, this patient

showed a free fraction of 22.4% due to severe hypoalbuminemia (2.4 g/dL). As a result of this finding, phenytoin was withheld for 12 h and subsequently dosage of phenytoin was

reduced to 400 mg from an initial dosing of 800 mg per day.

The patient continued to improve and was eventually discharged from the hospital in a stable condition [15].

Carbamazepine is metabolized to carbamazepine 10,11-epoxide, which is an

active metabolite. Although in the normal population epoxide concentrations may be 10À14% of total carbamazepine concentration, patients with

renal failure may show an over 40% epoxide concentration relative to the

carbamazepine concentrations. Monitoring active metabolite concentration

using chromatographic methods may be useful in these patients as there is

no immunoassay available for monitoring epoxide levels. Certain drug therapies, such as treatment with both valproic acid and carbamazepine, tend to



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increase the epoxide concentration. Monitoring the epoxide level may be

helpful if a patient experiences drug toxicity from an elevated epoxide level.

Primidone is an anticonvulsant that is metabolized to phenobarbital,

another anticonvulsant. Although pharmacological activities of primidone

are partly due to phenobarbital, primidone itself has anticonvulsant


For routine therapeutic drug monitoring of classical anticonvulsants, immunoassays are commercially available and can be easily adopted on various

automated analyzers. Since 1993, fourteen new antiepileptic drugs have been

approved: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. In general, these

antiepileptic drugs have better pharmacokinetic profiles, improved tolerability in patients, and are less involved in drug interactions compared to traditional anticonvulsants. However, felbamate is a very toxic drug with a risk of

fatal aplastic anemia, and the use of this drug is reserved for a few patients

where the benefits may override the risks. Therapeutic drug monitoring of

some of these new anticonvulsants is not needed, although a few drugs may

benefit from therapeutic drug monitoring. Therapeutic drug monitoring of

levetiracetam and pregabalin is justified in patients with renal impairment.

Monitoring active metabolites of oxcarbazepine (10-hydroxycarbazepine) has

some justification. In addition, therapy with lamotrigine, zonisamide, and

topiramate may also benefit from therapeutic drug monitoring. Usually chromatographic techniques are employed for therapeutic drug monitoring of

these newer anticonvulsants. These methods are usually free from interferences. However, there are commercially available immunoassays for lamotrigine, zonisamide, and topiramate.


Therapeutic drug monitoring of several cardioactive drugs, including digoxin,

procainamide, lidocaine, and quinidine, is routinely performed in clinical

laboratories due to the established correlation between serum drug concentrations and pharmacological response of these drugs. Moreover, drug toxicity can be mostly avoided by therapeutic drug monitoring. Digoxin

monitoring is challenging for following reasons:

Digoxin has a very narrow therapeutic window, and there are overlaps

between the therapeutic and toxic ranges. A classical therapeutic window

of 0.8À1.8 ng/mL is problematic. Although digoxin toxicity is common

with a digoxin level .2 ng/mL, some patients may experience digoxin

toxicity at a level of 1.5 ng/mL or higher.

14.15 Monitoring of Cardioactive Drugs

Digoxin immunoassays are affected by both endogenous and exogenous

factors (see Chapter 15).

Digoxin overdose can be treated with Digibind or DigiFab. For these

patients, progress of therapy must be monitored by measuring the free

digoxin level because the total digoxin level may be misleading due to

interference of Digibind/DigiFab with digoxin immunoassays.

Procainamide is metabolized to an active metabolite, N-acetyl procainamide

(NAPA). During therapeutic drug monitoring of procainamide, NAPA should

also be monitored because it contributes to the toxicity of procainamide. In

patients with renal insufficiency, NAPA concentration increases in blood due

to impaired renal clearance.


An 83-year-old patient with a history of adenocarcinoma of

prostate (stage D) and placement of a pacemaker 5 years

prior to his recent admission to the hospital was admitted for

a non-healing ulcer in his left foot (which required amputation). Two days prior to amputation, the patient showed

decreased urine output, atrial tachycardia, and shortness of

breath. He was admitted to the intensive care unit and was

treated with digoxin and furosemide. The next day he developed ventricular tachycardia and was managed with intravenous lidocaine. Later he was switched to intramuscular

procainamide. Three days later he developed renal insufficiency with a creatinine level of 5.5 mg/dL and BUN of

42 mg/dL. The patient showed a procainamide level of

14.1 μg/mL, but the N-acetyl procainamide (NAPA) level was

at the toxic level of 60.5 μg/mL. It was postulated that accumulation of NAPA in his blood was due to renal failure. The

combined procainamide and NAPA toxicity was treated with

hemodialysis, hemoperfusion, and combined hemodialysisÀhemoperfusion. He was eventually discharged from the

hospital when his creatinine was reduced to 3.3 mg/dL [16].

Key points to remember regarding therapeutic drug monitoring of lidocaine

and quinidine include:

Lidocaine cannot be given orally due to high first-pass metabolism.

However, tocainide, an analog of lidocaine, can be administered orally.

Lidocaine is strongly bound to α-acid glycoprotein, but free lidocaine is

not usually monitored.

Lidocaine after topical application may be absorbed significantly in some

patients, causing toxicity. Therapeutic drug monitoring of lidocaine is

needed for these patients.

Lidocaine is metabolized into monoethylglycinexylidide, and this

conversion can be used as a liver function test.

Quinidine is infrequently used today. Although this drug is strongly

bound to α-acid glycoprotein, free quinidine is usually not monitored.

Less frequently monitored cardioactive drugs include tocainide, flecainide,

mexiletine, verapamil, propranolol, and amiodarone. Tocainide was



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developed as an oral analog of lidocaine, because lidocaine cannot be

administered orally due to high first-pass metabolism; tocainide and lidocaine have similar electrophysiological properties.


Theophylline and caffeine are two anti-asthmatic drugs that require therapeutic drug monitoring. Theophylline is a bronchodilator and a respiratory stimulant effective in the treatment of acute and chronic asthma. The drug is readily

absorbed after oral absorption, but peak concentration may be observed

much later with sustained-release tablets. Theophylline is metabolized by

hepatic cytochrome P-450; altered pharmacokinetics of theophylline in disease states have been reported. In infants, theophylline is partly metabolized

to caffeine, but in adults this metabolite is not formed. Theophylline is

metabolized to 3-methylxanthine and other metabolites in adults.

Apnea with or without bradycardia is a common medical problem in premature infants. Caffeine is effective in treating apnea in neonates. Because the

effectiveness of caffeine therapy can be readily observed clinically, therapeutic

drug monitoring of caffeine is only indicated when caffeine toxicity is apparent from clinical symptoms, including tachycardia, gastrointestinal intolerance, and jitteriness. In addition, therapeutic drug monitoring of caffeine

is also indicated if a neonate is unresponsive to caffeine therapy despite a

high dose.


Tricyclic antidepressants (TCAs), including amitriptyline, doxepin, nortriptyline, imipramine, desipramine, protriptyline, trimipramine, and clomipramine were introduced in the 1950s and 1960s. These drugs have a narrow

therapeutic window, and therapeutic drug monitoring is essential for efficacy

of these drugs as well as to avoid drug toxicity. The efficacy of lithium in

acute mania and for prophylaxis against recurrent episodes of mania has

been well established. Therapeutic drug monitoring of lithium is essential for

efficacy as well as to avoid lithium toxicity. Key points to remember in therapeutic drug monitoring of antidepressants:

Although immunoassays are available for determination of tricyclic

antidepressants, such assays should only be used for diagnosis of

tricyclic overdose (usually total tricyclic antidepressant

concentrations .500 ng/mL are considered critical).

14.18 Monitoring of Immunosuppressants

For routine therapeutic drug monitoring of tricyclic antidepressants,

chromatographic techniques must be used (high-performance liquid

chromatography or gas chromatography) because only such methods can

differentiate between different tricyclics, for example, amitriptyline from

its metabolite nortriptyline. Immunoassays can provide a total

concentration only, because both amitriptyline and nortriptyline have

almost 100% cross-reactivity. This is true for other tricyclic


A common mistake for therapeutic drug monitoring of lithium is to

collect specimens in a lithium heparin tube (which will falsely elevate the

true lithium concentration). This must be avoided and either a sodium

heparin tube or serum specimen (with no anticoagulant, such as a redtop tube) must be collected for lithium analysis.


A 37-year-old woman delivered a female infant at full term

(birth weight: 3.1 kg). The mother was on 900 mg/day of lithium throughout the pregnancy, and her serum lithium level

was 0.9 mmol/L at the time of delivery and 0.7 mmol/L

(0.7 mEq/L) 11 days later. The infant was breastfed, and her

serum lithium level was undetectable at 3 days after birth;

the infant’s blood lithium level was increased to 0.7 mmol/L

at Day 6 and 1.1 mmol/L at Day 10. The authors questioned

the validity of the serum lithium level in the infant because

the infant showed no sign of lithium toxicity nor did she have

any renal insufficiency. Later it was found that the infant’s

blood was wrongly collected in a tube containing lithium

heparin as an anticoagulant. A blood specimen correctly

collected later from the infant showed an undetectable level

of lithium [17].

More recently introduced antidepressants are selective serotonin reuptake

inhibitors (SSRIs), for example, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. This class of drugs has a wide therapeutic index. Usually

most of these drugs do not require routine therapeutic drug monitoring, but

some drugs may benefit from infrequent monitoring, especially in certain

patient populations like children, the elderly, pregnant women, and individuals with intelligence disabilities.


Therapeutic drug monitoring of all immunosuppressants is important. Key

points are the following:

Immunosuppressant drugs cyclosporine and tacrolimus are calcineurin

inhibitors, but sirolimus and everolimus (the most recently approved



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drug that is a 2-hydroxyethyl derivative of sirolimus) are m-TOR

(mammalian target of rapamycin) inhibitors. All these drugs are

monitored in whole blood.

Everolimus was developed to improve pharmacokinetic parameters of

sirolimus. The half-life of sirolimus is 60 hours, but the half-life of

everolimus is 18À35 hours.

Mycophenolic acid is a potent non-competitive inhibitor of inosine

monophosphate dehydrogenase enzymatic activity and thus selectively

inhibits lymphocyte proliferation. This is the only immunosuppressant

that is monitored in serum or plasma.

In patients with uremia and hypoalbuminemia, monitoring free

mycophenolic acid can be clinically useful.

Although immunoassays are available for monitoring

immunosuppressants, metabolite interferences in the immunoassays are

a significant problem. Chromatographic methods, especially liquid

chromatography combined with tandem mass spectrometry, is a gold

standard for therapeutic drug monitoring of immunosuppressants.

Although cyclosporine, sirolimus, everolimus and mycophenolic acid can

be determined by high-performance liquid chromatography combined

with ultraviolet detector (HPLC-UV), tacrolimus cannot be monitored by

HPLC-UV due to lack of an absorption peak in the ultraviolet region.


The most commonly monitored antibiotics in clinical laboratories are aminoglycosides and vancomycin. The aminoglycoside antibiotics consist of two

or more amino-sugars joined by a glycosidic linkage to a hexose or aminocyclitol. These drugs are used in the treatment of serious and often

life-threatening systemic infections. However, aminoglycosides can produce

serious nephrotoxicity and ototoxicity. Aminoglycosides are poorly absorbed

from the gastrointestinal tract, and these drugs are administered intravenously or intramuscularly. Children have a higher clearance of aminoglycosides. Patients with cystic fibrosis usually exhibit altered pharmacokinetics of

the antibiotics. After a conventional dose of an aminoglycoside, a patient

with cystic fibrosis shows a lower serum concentration compared to a patient

not suffering from cystic fibrosis. Although there are several aminoglycosides

used in the United States, the most commonly monitored aminoglycosides

are tobramycin, amikacin, and gentamicin. Aminoglycosides are administered either in traditional dosing (2À3 times a day) or once daily. Other less

common types of dosing such as synergy dosing are also practiced. Key

points in therapeutic drug monitoring of aminoglycosides are as follows:

14.20 Monitoring of Antineoplastic Drugs

If aminoglycoside therapy is needed for three days or less, therapeutic

drug monitoring may not be needed.

During traditional dosing, a peak concentration blood level should be

drawn 30À60 minutes after each dose, and a trough concentration

specimen must be drawn 30 minutes prior to the next dose.

In once-daily dosing, a larger dose of aminoglycoside is administered

compared to traditional dosing. There is no firm established guideline for

therapeutic drug monitoring after once-daily dosing. Peak and trough

concentration can be monitored. Alternatively, a specimen can be drawn

6À14 hours after the first dose to calculate dosing intervals using various


During aminoglycoside therapy, serum creatinine must be monitored at

least twice a week to ensure there is no significant renal insufficiency.

Therapeutic drug monitoring is also frequently employed during vancomycin

therapy (vancomycin is not an aminoglycoside). The drug is excreted in the

urine with no metabolism. Vancomycin therapy warrants therapeutic drug

monitoring if the patient receives vancomycin for five or more days, receives

a higher dosage of vancomycin, or is receiving both vancomycin and aminoglycosides. Both peak and trough concentrations should be monitored.

Ranges for peak concentrations of 20À40 μg/mL have been widely quoted,

and a trough concentration range of 5À15 μg/mL has reasonable literature

support. A trough concentration of 5À15 μg/mL is recommended because

nephrotoxicity and other complications are observed at vancomycin concentrations higher than this level.

Rapid infusion of vancomycin may be associated with pruritus, a rash involving the upper torso, head and neck, and occasionally hypotension. Known as

“red man” or “red neck” syndrome, this phenomenon is caused by nonimmunologically mediated release of histamine and can be avoided by

slower administration of vancomycin over at least 60 minutes. Heparin and

vancomycin are incompatible if mixed in intravenous solution or infused one

after another through a common intravenous line. Aminophylline, amobarbital, aztreonam, chloramphenicol, dexamethasone, and sodium bicarbonate

are also incompatible with vancomycin if mixed in the same container.

However, there are other antibiotics which are monitored infrequently.

Examples of less frequently monitored antibiotics include ciprofloxacin,

chloramphenicol, isoniazid, rifampin, and rifabutin.


Methotrexate is a competitive inhibitor of dihydrofolate reductase, a key

enzyme for the biosynthesis of nucleic acids. The cytotoxic activity of this


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