International School of Asia and the Pacific – Kalinga

Pharmacy Department
Pharmaceutical Medicinal Organic Chemistry

Metabolic Changes of Drugs and Related Organic Compounds

A Quick Look at the Contents:

I. General Pathways of Drug Metabolism
II. Sites of Drug Biotransformation
III. Role of Cytochrome P450 Monooxygenases in Oxidative Biotransformations
IV. Oxidative Reactions
V. Reductive Reactions
VI. Hydrolytic Reactions
VII. Phase II or Conjugation Reactions
VIII. Factors Affecting Drug Metabolism

Chapter Overview

This chapter describes the human metabolic processes of various functional groups found
in therapeutic agents. For pharmacists to be good practitioners, it is necessary for them to
understand why certain drugs are contraindicated with other drugs.

Metabolism plays a central role in the elimination of drugs and other foreign compounds
(xenobiotics) from the body. Most organic compounds entering the body are relatively lipid
soluble (lipophilic). Xenobiotics then meet their metabolic fate through various enzyme systems
that change the parent compound to render it more water soluble (hydrophilic).

If lipophilic drugs, or xenobiotics, were not metabolized to polar, readily excitable water-
soluble products, they would remain indefinitely in the body, eliciting their biological effects.
Consequently, drug metabolism reactions have traditionally been regarded as detoxication (or
detoxification) processes. Occasionally, the parent compound is inactive when administered
and must be metabolically converted to a biologically active drug (metabolite). These types of
compounds are referred to as prodrugs.

I. General Pathways of Drug Metabolism

Drug metabolism reactions have been divided into two categories: phase I
(functionalization) and phase II (conjugation) reactions.

General Summary of Phase I and Phase II Metabolic Pathways

Phase I or Functionalization Reactions
Oxidative Reactions
- Oxidation of aromatic moieties
- Oxidation of olefins
- Oxidation at benzylic, allylic carbon atoms, and carbon atoms to carbonyl and imines
- Oxidation at aliphatic and alicyclic carbon atoms
- Oxidation involving carbon-heteroatom systems:
- Carbon – Nitrogen systems (aliphatic and aromatic amines; includes N-dealkylation,
oxidative deamination, N-oxide formation, N-hydroxylation)
- Carbon – Oxygen systems (O-dealkylation)
- Carbon – Sulfur systems (S-dealkylation, S-oxidation, and desulfuration)
- Oxidation of alcohol and aldehydes
- Other miscellaneous oxidative reactions
Reductive Reactions
- Reduction of aldehydes and ketones
- Reduction of nitro and azo compounds
- Miscellaneous reductive reactions
Hydrolytic Reactions
- Hydrolysis of esters and amides
- Hydration of epoxides and arenes oxides by epoxide hydrase
 Phase II or Conjugation Reactions
Glucuronic acid conjugation
Sulfate conjugation
Conjugation with glycine, glutamine, and other amino acids
Glutathione or mercapturic acid conjugation
Acetylation
Methylation

The purpose of Phase I reactions is to introduce a functional polar group(s) into the
xenobiotic molecule to produce a more water-soluble compound. This can be achieved by direct
introduction of the functional group or by modifying or “unmasking” existing functionalities.
Although phase I reactions may not produce sufficiently hydrophilic or inactive metabolites, they
generally tend to provide a functional group or “handle” on the molecule that can undergo
subsequent phase II reactions.

The purpose of Phase II reactions is to attach small, polar, and ionizable endogenous
compounds such as glucuronic acid, sulfate, glycine, and other amino acids to the functional
handles of phase I metabolites or parent compounds that already have suitable existing functional
groups to form water-soluble conjugated products.

To illustrate, consider the principal psychoactive constituent of marijuana, ▲9-

tetrahydrocannabinol. This lipophilic molecule undergoes allylic hydroxylation to give 11-hydroxy-
▲9-THC in humans. More polar than its parent compound, the 11-hydroxy metabolite is further
oxidized to the corresponding carboxylic acid derivative ▲9-THC-11-oic acid, which is ionized at
physiological pH. Subsequent conjugation of this metabolite with glucuronic acid leads to water-
soluble products that are readily eliminated in the urine.

Enzyme Inhibitors Enzyme Inducers

“sickfaces.com” “GPP PARK Sa Mall”

- Sodium valproate - Griseofulvin

- Isoniazid - Phenobarbital (Barbiturates)
- Cimetidine - Phenytoin
- Ketoconazole - Phenylbutazone
- Fluconazole - Alcohol (chronic)
- Alcohol (acute) - Rifampicin
- Ciprofloxacin - Carbamazepine
- Erythromycin - Sulfonylurea
- Sulfonamide - Meprobamate
- Chloramphenicol
- Omeprazole Herbs:
- Metronidazole - St. John’s Wort

Herbs:
- Grape fruit
- Valencia oranges

II. Sites of Drug Biotransformation

Although biotransformation reactions may occur in many tissues, the liver is, by far, the
most important organ in drug metabolism and detoxification of endogenous and exogenous
compounds. Orally administered drugs that are absorbed into the bloodstream through the GI
tract must pass through the liver before being further distributed into body compartments.
Therefore, they are susceptible to hepatic metabolism known as the first-pass effect before
reaching the systemic circulation. Several drugs are metabolized extensively by the first-pass
effect. The following list includes some of those drugs:
Isoproterenol Morphine Propoxyphene
Lidocaine Nitroglycerin Propranolol
Meperidine Pentazocine Salicylamide

Some drugs (e.g., lidocaine) are removed so effectively by first-pass metabolism that they
are ineffective when given orally. Nitroglycerin is administered bucally to bypass the liver.
 Because most drugs are administered orally, the intestine appears to play an important
role in the extrahepatic metabolism of xenobiotics.

Although other tissues, such as kidney, lungs, adrenal glands, placenta, brain, and skin,
have some drug-metabolizing capability, the biotransformations that they carry out are often
more substrate selective and more limited to particular types of reaction.

III. Role of Cytochtome P450 Monooxygenases in Oxidative Biotransformations

Of the various phase I reactions that are considered, oxidative biotransformation

processes are, by far, the most common and important in drug metabolism.

The enzyme systems carrying out this biotransformation are referred to as mixed-
function oxidases or monooxygenases.

Cytochrome P450 Enzymes Nomenclature

CYP – Arabic number – Capital letter – Arabic number

1. CYP: Cytochrome P450 enzymes
2. Arabic number: Family (CYP1, CYP2, CYP3, etc.)
3. Capital letter: Subfamily (CYP1A, CYP2C, CYP3A, etc.)
4. Arabic number: Individual enzyme in a subfamily (CYP1A2, CYP2C9, CYP2D6, CYP2E1,
CYP3A4)

The CYP enzymes are heme proteins. The heme portion is an iron-containing porphyrin called
protoporphyrin IX, and the protein portion is called the apoprotein. CYP is found in high
concentrations in the liver, the major organ involved in the metabolism of xenobiotics. The name
cytochrome P450 is derived from the fact that the reduced (Fe2+) form of this enzyme binds
with carbon monoxide to form a complex that has a distinguishing spectroscopic absorption
maximum at 450 nm.

The CYP monooxygenases are located in the endoplasmic reticulum, a highly organized and
complex network of intracellular membranes that is particularly abundant in tissues such as the
liver. When these tissues are disrupted by homogenization, the endoplasmic reticulum loses its
structure and is converted into small vesicular bodies known as microsomes.