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22 ESSENTIAL PHARMACOLOGY
2. Most (but not all) oxidative reactions are carried out by numer-
ous, distinct cytochrome p450 systems:
(a) These are mixed- function oxidases that utilize NADPH
and O
2
.
There are 12 gene families for p450 systems in humans;
most drug metabolism is catalyzed by three of these: CYP1,
CYP2, and CYP3.
(b) The oxidation of a drug by a cytochrome p450 can be thought
of as a “molecular fire” resulting in the formation of a “burn-
ing ember” - a highly unstable and reactive intermediate
that can have toxic effects (see Figure4.1).
(c) The toxic effects of the metabolic intermediates may lead to
hepatic necrosis, e.g., acetaminophen metabolites, or to car-
cinogenic or teratogenic compounds (see Figure4.2).
Drug
Oxidized
drug
+
H
2
O
[Fe
3+
]
Drug-[Fe
3+
]
Reduced
flavoprotein
NADP
+
*
Cytochrome
P-450
Cytochrome
P-450
reductase
Drug-[Fe
2+
]-O
2
Drug-[Fe
2+
]
Oxidized
flavoprotein
NADPH
O
2
*
Denotes contribution of a second electron and two hydrogen ions from NADH-flavoprotein-
cytochrome
b
5
or from NADPH-flavoprotein.
Figure4.1 Major components of the hepatic cytochrome P450 system.
+
cytochrome.
SOURCE:
th
Biotransformation of Drugs 23
3. Induction of microsomal enzymes
(a) Activation of specific transcription factors by a drug leads to
a proliferation of smooth endoplasmic reticulum (ER) with
increases in the amount of a wide range of cytochrome p450
and glucuronide conjugating enzyme systems resident in
the ER. Phenobarbital is one of the most notorious of the
“inducers”.
R
(a)
(b)
R
OX
R
O
NCH
3
HC
O
OH
Acetaminophen
Tissue
adduct
NCH
3
HO C
O
Glutathione
adduct
Glutathione
adduct
Mixed-
function
Oxidase
Glutathione
aryltransferase
Glutathione
aryltransferase
Alcohol
Diol
[O]
Tissue
adduct
OH
N
O
CH
3
C
O
NC
H
3
HC
O
OH
X
Mixed-
function
Oxidase
Figure4.2
SOURCE:
th
24 ESSENTIAL PHARMACOLOGY
(b) Polycyclic hydrocarbons (present in cigarette smoke and
charbroiled meats) are more selective inducers of a distinct
set of terminal oxidases.
(c) Important for drug interactions and pharmacokinetic
tolerance
– cigarette smokers may require higher dosing regimens
because of rapid drug metabolism
– use of one drug can lead to increased clearance of an unre-
lated drug if it is metabolized by the same enzyme
– drugs that are taken chronically (e.g., anticonvul-
sants) may be cleared more rapidly after 1– 2 weeks of
administration– this must be taken into account when
trying to establish “steady- state” dosage
4. Drug metabolizing systems have a very high capacity so that
competitive interactions between drugs are uncommon. How-
ever, they do occur, particularly when one drug is present at a
concentration that saturates the relevant enzyme. For example,
liver alcohol dehydrogenase can readily be saturated by ethanol.
This explains why methanol poisoning can be treated by admin-
istering ethanol, which competitively inhibits the formation of
toxic formaldehyde from methanol.
However, a few drugs are notorious for “non- competitive”
inhibition of drug metabolism, e.g., the histamine H2 antagonist
cimetidine or the macrolide antibiotic erythromycin, which
can reduce the metabolism of a large number of drugs. Such
compounds should be remembered as they are frequently
encountered during medical practice.
5. Constitutive metabolic capacity can vary dramatically
(a) Developmental factors or age- dependence – drug metabo-
lism is low in the neonate, higher in children (more liver/
kg), and then often declines in the elderly. Drug dosing regi-
mens need to be adjusted accordingly.
(b) Genetic factors – up to sixfold or more differences among
individuals can occur, and these polymorphisms are very
common. For example, some 50% of Americans have reduced
acetylating enzyme systems for the metabolism of caffeine.
Biotransformation of Drugs 25
Some people need more than one cup of coffee to get going
in the morning (“fast acetylators”); others can’t sleep if they
drink coffee after 4 PM (“slow acetylators”).
6. Non- microsomal biotransformation is important for some
classes of drugs
(a) Conjugation with acetate, glycine, glutathione, or sulfate
occurs in the cytosol.
(b) Hydrolysis– occurs in the cytosol and also in plasma.
(c) Oxidation in cytosol or mitochondria by flavoproteins (e.g.,
monoamine oxidase (mitochondria), alcohol dehydrogenase
[cytosolic]).
(d) Although there can be sixfold or more variation among
individuals for these enzymes (genetic basis), no induc-
tion phenomena are known, in contrast to the cytochrome
p450 enzymes.
26
Chapter 5
Excretion of Drugs
T
he kidney is usually the most important organ for excretion
of drugs, their metabolites, and drug conjugates. The basis
of excretion of drugs from the kidney depends on a com-
prehensive mechanism to deal with foreign compounds that the
organism has not encountered previously and that might be dan-
gerous. A poorly designed excretion system might depend on the
evolution of specific transport proteins to recognize all unknown
compounds. How could this happen? Instead, the kidney has
evolved a strategy that does not depend on the recognition of
unknown compounds. It simply “throws everything out” and then
takes back desired compounds. Specifically, the glomerular appara-
tus acts as a non-selective filter to excrete all small molecules from
the bloodstream and then depends on specific transport proteins in
the kidney tubules that have evolved to recognize molecules needed
for life processes, e.g., glucose, and to transport them back into the
bloodstream from the effluent in the tubule lumen.
Excretion ofDrugs 27
However, there are additional classes of transport proteins
in the tubules that do recognize some compounds and actually
enhance their excretion above amounts filtered alone. An interest-
ing historical example is penicillin, which is actively excreted into
the urine by a transporter that recognizes a range of acidic com-
pounds. When penicillin was initially introduced as an antibiotic
the quantities were limited, and it was very expensive. The drug
probenecid is an inhibitor of this transport enzyme in the tubules
and was given to increase the lifetime of penicillin in circulation.
The excretory process in the kidney is less effective for drugs
that are hydrophobic and can cross membranes. After filtration,
these drugs may reenter circulation by passive diffusion back
into the bloodstream as the urine is concentrated in the tubules.
Effective elimination of hydrophobic drugs may depend on metabo-
lism to hydrophilic forms or conjugation with molecules such as
glucuronic acid that are themselves hydrophilic.
The absolute rate of renal excretion depends on the plasma
concentration of free drug and the glomerular filtration rate (GFR).
Passive reabsorption of uncharged species occurs in proximal and
distal tubules and also depends on the rate of flow of tubular urine.
Secretion (and active uptake) of certain organic cations and
anions occurs in proximal tubules.
Some transport systems also recognize conjugated drugs (e.g.,
formed by glucuronic acid conjugating enzymes and others).
Biliary excretion of free and conjugated drugs is sometimes
important; however, hydrolysis of conjugates by intestinal flora
can lead to reabsorption and “enterohepatic circulation” of drugs
extending their lifetime in circulation.
The lungs are the major route of excretion of anesthetic gases.
Minor routes of excretion include saliva (may be used for drug
testing), sweat, and milk (of significance for nursing infants).
28
Clinical Pharmacokinetics
6.1 Introduction
It is of paramount importance to select the correct drug for treating
a pathology. However, it is not enough to pick the right drug. One
must also decide how much drug to administer and how often.
This is the domain of clinical pharmacokinetics, a mathematical
discipline leading to quantitative answers. In order to understand
or design rational dosing regimens for drugs, it is necessary to know
some basic pharmacokinetic concepts and how to use a few rela-
tively simple equations. The ultimate goal is to administer sufficient
drug to a patient to achieve a therapeutic concentration of free drug
at the sites of action without generating concentrations that are
associated with dangerous or unacceptable side effects. Many drugs
are given on a long-term basis, and it is important to realize that
maintenance dosage is aimed at replacing the drug that has been
eliminated between doses. Thus, at the steady state, the dosing rate
must equal the elimination rate:
Dosing rate rate of elimination
Chapter 6
Clinical Pharmacokinetics 29
Here we will first define the pharmacokinetic parameters and
variables one must be familiar with in order to establish this desired
steady state. Then we will develop a simple model of the patient and
the relationships between these terms. This will be an ideal model,
but it will yield clinically useful approximations in the case of
most drugs. Using this model as a frame of reference, we will then
point out the types of exceptions that are likely to be encountered
in practice. Although the model may seem complex as it involves
exponential terms in the mathematical description, we will be able
to use the model to generate some simple formulae that can be
readily used– even by the medical resident who has not slept for
30 hours!– to make useful pharmacokinetic calculations.
6.2 Pharmacokinetic Parameters andVariables
Units. The quantities we will deal with all have associated units. It
is essential to keep track of these units as they will remind you of
whether you are using the right relationship (equation), and they
may prevent you from making an error of several orders of magni-
tude in calculating a dose.
You may encounter several conventions for writing units. All of
the following are equivalent:
mg/min per kg mg/min- kg mg/min/kg mg min
−1
kg
−1
(kilogram may be seen as kg or Kg)
1. Plasma drug concentration, C μg/ml, mg/ml, etc.
Typically this is the total concentration of the drug. Some amount
of the drug will be bound to plasma proteins. It is not necessarily
the concentration of drug at the site of the relevant drug target,
but it is usually the only information readily available. You will
attempt to maintain a given target steady- state concentration, C
ss
μg/ml, that has been shown in clinical trials to achieve optimum
therapeutic effects.
2. Dose, D mg, or mg/kg
This is the amount (typically a mass, sometimes a volume) of
drug given at a single point in time. It may be normalized in
30 ESSENTIAL PHARMACOLOGY
terms of the mass of the patient, or a standard dose may be appli-
cable to all patients (e.g., two aspirin).
3. Dosing rate or Dosage, D.R. mg/min per kg.
This represents the total amount of drug administered per unit
time, often normalized per kg of patient weight. If the patient’s
weight is known, the “per kg” may be “absorbed” into the value
of D.R. For example, a D.R. of 6 mg/min per kg for a 70 kg patient
is equivalent to 420 mg/min. If the drug is given by intravenous
infusion, the dosing rate is usually constant in time. With oral or
other routes of administration it obviously fluctuates, but the aver-
age over time is usually taken as the dosing rate for the purpose of
making pharmacokinetic calculations, e.g., 50 mg/h per kg.
Be careful not to confuse Dose and Dosage. Remember that
Dosage involves an element of time, the Dosage Interval:
Dosage Dose Dosage Interval/
e.g., 100 mg every 8 hours
4. Bioavailability, F (dimensionless)
This is the fraction of the drug administered that actually enters
the plasma. If the value of F is less than 1, then some drug is
not absorbed or is metabolized before entering the systemic
circulation.
5. Volume of distribution, V
d
, l/kg
This is the “apparent” volume in the patient into which a drug
has dissolved after administration. It is a derived parameter that
may not represent a physical volume. It is determined by admin-
istering a given dose and measuring the resulting plasma con-
centration.
Vl kg doseplasmaconcentrationDmg kg Cm
gl
d
// // /
If some of the drug is bound to adipose tissue, for example, the
concentration in the plasma will be lower than expected. We deal
with this situation by saying the volume of distribution is large.
Clinical Pharmacokinetics 31
As an example of this concept, suppose somebody gave you a
1- gallon opaque jug containing 2 l of water (Figure 6.1). If you dis-
solved 10 mg of a drug in the jug (shaking it well and letting it stand
for a while), an aliquot taken from the top of the jug would contain
5 mg/l of the drug, and you would calculate that the jug contained 2 l.
Now suppose somebody gave you a 1- gallon opaque jug contain-
ing 2 l of water that also contained sufficient granules of charcoal to
bind exactly 9 mg of a drug (Figure 6.2). If you dissolved 10 mg of the
drug in the jug an aliquot taken from the top of the jug would con-
tain only 0.5 mg/l and you would calculate that the jug contained 20 l
(10 mg/0.5 mg/l)– a surprise for a vessel whose capacity is less than 4 l!
Hopefully, you won’t be confused when you encounter drugs
with an apparent Vd in excess of 30 l/kg (e.g., desipramine) in
subjects whose total body water can’t be much more than 0.6– 0.65 l/kg.
2 l
“Dose”
10 mg
C =
C = 5 mg/l
= 2 l
D
V
D
V
D
=
D
C
=
10 mg
5 mg/l
Figure6.1 Calculation of the volume of distribution when a drug is not
2 l
(9 mg)
“Dose”
10 mg
C = 0.5 mg/l
= 20 l
V
D
=
D
C
=
10 mg
0.5 mg/l
Figure6.2 Calculation of the volume of distribution when a drug is partially