Drug Metabolism

15 Metabolite
Pharmacokinetics
OBJECTIVES
After completing this chapter you should be able to
• Discuss the importance of studying metabolite pharmacokinetics after a

single and repeated drug administration
• Describe the metabolic pathways involved in the formation of the metabo-
lites after parent drug administration
• Discuss the models that can be used to describe the formation of metabo-
lites after administration of the parent drug
• Identify the factors that affect the metabolite formation after administration
of the parent drug
• Calculate the different metabolite pharmacokinetic parameters after IV
administration of the parent drug
• Analyze the effect of changing each of the drug and metabolite pharmaco-
kinetic parameters on the drug and metabolite profiles after a single drug
administration
• Analyze the effect of changing each of the drug and metabolite pharmaco-
kinetic parameters on the drug and metabolite profiles at steady state dur-
ing multiple drug administration
15.1 INTRODUCTION
Drug elimination from the body involves excretion of the unchanged drug through
various excretion pathways or drug metabolism via the different metabolic path-
ways. Drug metabolism involves enzymatic or chemical modification of the chemi-
cal structure of the drug molecule to form a new chemical entity called metabolite.
Studying of the metabolite pharmacokinetics is important because in most cases the
effect of the drug disappears when the drug is metabolized to pharmacologically
inactive metabolites. However, some of the formed metabolites are pharmacologi-
cally active, and some metabolites are reactive and can cause serious adverse effects.
Procainamide is an antiarrhythmic drug metabolized to n-acetyl procainamide
(NAPA) that also possesses antiarrhythmic activity similar to the parent drug. So the
antiarrhythmic effect observed after administration of procainamide results from
both the parent drug and the metabolite. Cocaethylene (CE) is a cocaine metabolite
formed only when cocaine is abused simultaneously with alcohol, which is a com-
monly used combination. This metabolite is more lethal than cocaine with regard to
253
254 Basic Pharmacokinetics
the cardiovascular complications and has central nervous system stimulant activity
similar in potency to that of cocaine. Also, the antiepileptic drug carbamazepine is
metabolized to carbamazepine epioxide that is responsible for most of the parent
drug toxicity. So studying the factors that affect the metabolite formation and elimi-
nation and the general pharmacokinetic behavior of the metabolites is necessary for
accurate prediction of the therapeutic and the adverse effects produced by the parent
drug and its metabolite(s).
15.2 DRUG METABOLIC PATHWAYS

Drug metabolism, also referred to as drug biotransformation or drug detoxifica-
tion, usually involves enzymatic modification of the chemical structure of a drug
to form one or more metabolites. This modification of the drug chemical structure
causes change (increase or decrease) in the pharmacological and adverse effects of
the drugs. The metabolites are usually more polar than their parent drugs and are
excreted rapidly from the body by the different excretion mechanisms. However,
there are exceptions to this general rule where the metabolite half-life is longer than
that of the parent drug. Drug metabolism is usually mediated by specialized enzyme
systems that can be induced or inhibited resulting in modification of the rate of
the drug metabolic process. Also, different drugs that are metabolized through the
same metabolic pathway can compete for the same enzyme system. The drug with
higher affinity to the enzyme slows or inhibits the metabolism of the drug with lower
enzyme affinity. Furthermore, many nutritional, environmental, and genetic factors
in addition to alcohol and smoking can affect the activity of the drug metabolizing
enzymes. So drug metabolism is one of the important mechanisms by which clini-
cally significant drug–drug interactions occurs.
15.2.1 Classification of the Metabolic Reactions

The drug metabolic pathways are classified into two major groups of reactions: phase I
and phase II metabolic reactions [1].
15.2.1.1 Phase I Metabolic Reactions

These metabolic reactions are also known as functionalization reactions or non-
synthetic reactions. They involve the introduction of polar function groups such as
hydroxyl group, primary amines, carboxylic acids, etc., to form more polar metabo-
lites. Phase I metabolic reactions do not have to occur before phase II reactions
because some drugs are metabolized directly by phase II reactions without going
through phase I metabolism. Also, there are examples of some metabolites that are
formed by phase II metabolic reactions that undergo further metabolism through
phase I metabolic reactions. The most common phase I reactions include oxidation,
reduction, and hydrolysis. Oxidation reactions usually involve addition of oxygen or
removal of hydrogen such as aliphatic and aromatic hydroxylation, n-dealkylation,
o-dealkylation, s-dealkylation, n-oxidation, s-oxidation, deamination, dehalogena-
tion, etc. These oxidation reactions are mediated mainly by the cytochrome P450
(CYP450) monooxygenase enzyme system in addition to other enzyme systems.
Metabolite Pharmacokinetics 255
TABLE 15.1
Most Common Enzyme Systems Involved in the Different
Types of Phase I and Phase II Metabolic Reactions
Phase Reaction Type Enzyme System
I Oxidation Cytochrome P450 monooxygenase system
Flavin-containing monooxygenase system
Alcohol dehydrogenase
Aldehyde dehydrogenase
Monoamine oxidase
Co-oxidation by peroxidases
Reduction NADPH-cytochrome P450 reductase
Reduced cytochrome P450
Hydrolysis Esterases
Amidases
Epoxide hydrolase
II Methylation Methyltransferase
Sulfation Glutathione S-transferases
Sulfotransferases
Acetylation N-acetyltransferase
Amino acid N-acyl transferases
Glucuronidation UDP-glucuronosyltransferases
The phase I reduction reactions involve removal of oxygen or addition of hydro-

gen. Most of the products of the oxidative metabolism are substrates for the reduc-
tive reactions causing redox cycling, with the equilibrium between the oxidation
and reduction reactions determined by the balance of cofactors and oxygen con-
centration. The phase I hydrolysis reactions include hydrolysis of esters, hydroly-
sis of amides including the peptides, and hydration of epoxides. The most common
enzyme systems involved in phase I metabolism are listed in Table 15.1.
15.2.1.2 Phase II Metabolic Reactions
These metabolic reactions are also known as conjugation reactions or synthetic reac-
tions. Phase II reactions usually involve formation of conjugates between the drug
and other compounds such as glucuronic acid, glutathione, amino acids, and others.
The most common sites on the drug chemical structure where conjugation reactions
occur include carboxyl, hydroxyl, amino, and sulfhydryl groups. The products of
phase II metabolic reactions have increased molecular weight and are usually inac-
tive. The most common enzyme systems involved in phase II metabolism are listed
in Table 15.1.
15.2.2 Cytochrome P450

CYP450 is a superfamily of metabolizing enzymes that are responsible for approxi-
mately 75% of the total drug metabolism in humans. It contains heme cofactors, so
it is considered a hemoprotein. The reduced iron in the heme cofactor can produce

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15 Metabolite

• Discuss the importance of studying metabolite pharmacokinetics after a

15.2 DRUG METABOLIC PATHWAYS

15.2.1 Classification of the Metabolic Reactions

15.2.1.1 Phase I Metabolic Reactions

The phase I reduction reactions involve removal of oxygen or addition of hydro-

15.2.2 Cytochrome P450

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