Pharmacokinetics

Lecture 4
DRUG CLEARANCE THROUGH METABOLISM
Once a drug enters the body, the process of elimination begins. The three
major routes of elimination are hepatic metabolism, biliary elimination,
and urinary elimination. Together, these elimination processes decrease
the plasma concentration exponentially. That is, a constant fraction of the
most drug present is eliminated in a given unit of time
drugs are eliminated according to first-order kinetics, although some,
such as aspirin in high doses, are eliminated according to zero-order
or nonlinear kinetics. Metabolism leads to production of products with
increased polarity, which allows the drug to be eliminated. Clearance
(CL) estimates the amount of drug cleared from the body per unit of time.
Total CL is a composite estimate reflecting all mechanisms of drug elimination
and is calculated as follows:
t1/ 2= 0 693 *Vd / cl
where t1/2 is the elimination half-life, Vd is the apparent volume of distribution,
and 0.693 is the natural log constant. Drug half-life is often used as
a measure of drug CL, because, for many drugs, Vd is a constant.
Kinetics of metabolism
1. First-order kinetics: The metabolic transformation of drugs is
catalyzed by enzymes, and most of the reactions obey Michaelis-Menten kinetics.
2. Zero-order kinetics: With a few drugs, such as aspirin, ethanol,
and phenytoin, the doses are very large. Therefore, [C] is much
greater than Km, and the velocity equation becomes
The enzyme is saturated by a high free drug concentration,
and the rate of metabolism remains constant over time. This is
called zero-order kinetics (also called nonlinear kinetics). A constant
amount of drug is metabolized per unit of time. The rate
of elimination is constant and does not depend on the drug
concentration
Reactions of drug metabolism
The kidney cannot efficiently eliminate lipophilic drugs that readily
cross cell membranes and are reabsorbed in the distal convoluted
tubules. Therefore, lipid-soluble agents are first metabolized into more
polar (hydrophilic) substances in the liver via two general sets of reactions,
called phase I and phase II .
1. Phase I: Phase I reactions convert lipophilic drugs into more polar
molecules by introducing or unmasking a polar functional group,
such as –OH or –NH2. Phase I reactions usually involve reduction,
oxidation, or hydrolysis. Phase I metabolism may increase,
decrease, or have no effect on pharmacologic activity.
a. Phase I reactions utilizing the P450 system: The phase I
reactions most frequently involved in drug metabolism are catalyzed
by the cytochrome P450 system (also called microsomal
mixed-function oxidases). The P450 system is important for the
metabolism of many endogenous compounds (such as steroids,
lipids) and for the biotransformation of exogenous substances
(xenobiotics). Cytochrome P450, designated as CYP,
is a superfamily of heme-containing isozymes that are located
in most cells, but primarily in the liver and GI tract.
Nomenclature: The family name is indicated by the Arabic
number that follows CYP, and the capital letter designates
the subfamily, for example, CYP3A .A second
number indicates the specific isozyme, as in CYP3A4.
Specificity: Because there are many different genes that
encode multiple enzymes, there are many different P450
isoforms. These enzymes have the capacity to modify a
large number of structurally diverse substrates. In addition,
an individual drug may be a substrate for more than
one isozyme. Four isozymes are responsible for the vast
majority of P450-catalyzed reactions. They are CYP3A4/5,
CYP2D6, CYP2C8/9, and CYP1A2
Considerable amounts of CYP3A4 are found in intestinal
mucosa, accounting for first-pass metabolism of drugs such
as chlorpromazine and clonazepam.
Genetic variability: P450 enzymes exhibit considerable
genetic variability among individuals and racial groups.
Variations in P450 activity may alter drug efficacy and the
risk of adverse events. CYP2D6, in particular, has been
shown to exhibit genetic polymorphism. CYP2D6 mutations
result in very low capacities to metabolize substrates. Some
individuals, for example, obtain no benefit from the opioid
analgesic codeine, because they lack the CYP2D6 enzyme
that activates the drug. Similar polymorphisms have been
characterized for the CYP2C subfamily of isozymes. For
instance, clopidogrel carries a warning that patients who
are poor CYP2C19 metabolizers have a higher incidence
of cardiovascular events (for example, stroke or myocardial
infarction) when taking this drug. Clopidogrel is a prodrug,
and CYP2C19 activity is required to convert it to the
active metabolite. Although CYP3A4 exhibits a greater than
10-fold variability between individuals, no polymorphisms
have been identified so far for this P450 isozyme.
Inducers: The CYP450-dependent enzymes are an
important target for pharmacokinetic drug interactions. One
such interaction is the induction of selected CYP isozymes.
Xenobiotics (chemicals not normally produced or expected
to be present in the body, for example, drugs or environmental
pollutants) may induce the activity of these enzymes.
Certain drugs (for example, phenobarbital, rifampin, and
carbamazepine) are capable of increasing the synthesis
of one or more CYP isozymes. This results in increased
biotransformation of drugs and can lead to significant
decreases in plasma concentrations of drugs metabolized
by these CYP isozymes, with concurrent loss of pharmacologic
effect. For example, rifampin, an antituberculosis
drug , significantly decreases the plasma
concentrations of human immunodeficiency virus (HIV) protease
inhibitors, thereby diminishing their ability to suppress
HIV replication. St. John’s wort is a widely used herbal product
and is a potent CYP3A4 inducer. Many drug interactions
have been reported with concomitant use of St. John’s wort.
Figure 1.18 lists some of the more important inducers for
representative CYP isozymes. Consequences of increased
drug metabolism include 1) decreased plasma drug concentrations,
2) decreased drug activity if the metabolite is inactive
3) increased drug activity if the metabolite is active, and
4) decreased therapeutic drug effect.
Inhibitors: Inhibition of CYP isozyme activity is an important
source of drug interactions that lead to serious adverse
events. The most common form of inhibition is through competition
for the same isozyme. Some drugs, however, are
capable of inhibiting reactions for which they are not substrates
(for example, ketoconazole), leading to drug interactions.
Numerous drugs have been shown to inhibit one
or more of the CYP-dependent biotransformation pathways
of warfarin. For example, omeprazole is a potent inhibitor
of three of the CYP isozymes responsible for warfarin
metabolism. If the two drugs are taken together, plasma
concentrations of warfarin increase, which leads to greater
anticoagulant effect and increased risk of bleeding.
[Note: The more important CYP inhibitors are erythromycin,
ketoconazole, and ritonavir, because they each inhibit several
CYP isozymes.] Natural substances may also inhibit drug
metabolism. For instance, grapefruit juice inhibits CYP3A4
and leads to higher levels and/or greater potential for toxic
effects with drugs, such as nifedipine, clarithromycin, and
simvastatin, that are metabolized by this system.
. Phase I reactions not involving the P450 system: These
include amine oxidation (for example, oxidation of catecholamines
or histamine), alcohol dehydrogenation (for example,
ethanol oxidation), esterases (for example, metabolism of
aspirin in the liver), and hydrolysis (for example, of procaine).
. Phase II: This phase consists of conjugation reactions. If the
metabolite from phase I metabolism is sufficiently polar, it can be
excreted by the kidneys. However, many phase I metabolites are
still too lipophilic to be excreted. A subsequent conjugation reaction
with an endogenous substrate, such as glucuronic acid, sulfuric
acid, acetic acid, or an amino acid, results in polar, usually more
water-soluble compounds that are often therapeutically inactive. A
notable exception is morphine-6-glucuronide, which is more potent
than morphine. Glucuronidation is the most common and the most
important conjugation reaction. [Note: Drugs already possessing
an –OH, –NH2, or –COOH group may enter phase II directly and
become conjugated without prior phase I metabolism.] The highly
polar drug conjugates are then excreted by the kidney or in bile