Saint Louis University | Department of Pharmacy

Pharm 222: Pharmaceutical and Medicinal Organic Chemistry (Lecture)

Pharm 222: Pharmaceutical and Medicinal Organic Chemistry

Chapter III: Drug Metabolism (Part I)
Topics:
A. Principles of Drug Metabolism

B. First- Pass Effect

C. Consequences of Metabolism

D. Sites of Metabolism/Drug Biotransformation

E. Cytochrome P-450

F. Enzyme Inhibition and Enzyme Induction

A. Principles of Drug Metabolism

Most organic compounds (drugs and xenobiotics) entering the body are relatively
lipid soluble (lipophilic). To be absorbed, they must traverse the lipoprotein
membranes of the lumen walls of the GIT.

Then, once in the bloodstream, these molecules can diffuse passively through other
membranes and be distributed effectively to reach various target organs to exert their
pharmacological actions.

• If lipophilic drugs were not metabolized to polar, readily excretable water-

soluble products, they would remain indefinitely in the body, eliciting their
biological effects. (lipophilic drugs undergo tubular reabsorption and thus are not excreted through the urine)

• Xenobiotics then meet their metabolic fate through various enzyme systems that change the parent compound to
render it more water soluble (hydrophilic). Once the metabolite is sufficiently water soluble, it may be excreted from
the body.

Thus, the formation of water-soluble metabolites not only enhances drug elimination, but also leads to compounds that
are generally pharmacologically inactive and relatively nontoxic.

Main Purpose of Metabolism: conversion of drugs into polar, water soluble products that are readily excretable

B. First Pass Effect

- Happens when an orally administered drug is absorbed into bloodstream through GIT passes through the liver
before being further distributed

- Examples:

Isoproterenol
Pentazocine

Lidocaine
Propoxyphene

Meperidine
Propranolol

Morphine
Salicylamide 

Nitroglycerin

Intestinal mucosa
- Contains CYP3A4 isozyme and P-glycoprotein (PGP) that can
capture drug and secrete it back to intestinal tract

- Plays a role in extra hepatic metabolism of xenobiotics

- Example: Isoproterenol (sulfate conjugation); aromatic azo and nitro

drugs (bacterial flora)

Prepared by: Aldrex B. Dacawe, RPh, MS Pharm

Lectured by: Mary Christine S. Cariño, RPh, MS Pharm Page 1 of 4

 Saint Louis University | Department of Pharmacy

Pharm 222: Pharmaceutical and Medicinal Organic Chemistry (Lecture)

C. Consequences of Metabolism:

A. May yield inactive metabolites

- Some metabolites are inactive meaning their pharmacologically active parent compounds become inactivated/
detoxified.

- Examples:

1. Hydrolysis of procaine to p- aminobenzoic acid & diethylethanolamine

2. Oxidation of 6- mercaptopurine to 6- mercapturic acid

B. May retain similar activity

- Certain metabolites retain pharmacological activity of their parent compounds to greater or lesser degree.

- Examples:

1. Imipramine is demethylated to the essentially equiactive antidepressant, desipramine

2. Acetohexamide is reduced to the more active hypoglycemic, I- hydroxyhexamide

3. Codeine is demethylated to the more active analgesic, morphine

C. May produce metabolites with altered activity

- Some metabolites develop activity which is different from that of their parent compound.

- Examples:

1. The antidepressant iproniazid is dealkylated to the antitubercular drug, Isoniazid

2. The vitamin retinoic acid (Vitamin A) is isomerized to the anti- acne agent, isoretinoic acid

D. Production of bioactivated metabolites

- Some pharmacologically inactive parent compounds are converted to active compounds within the body. These
parent compounds are known as prodrugs.

- Example:

1. The prodrug enalapril is hydrolyzed to enalaprilat

2. The prodrug sulindac, a sulfoxide, is reduced to the active sulfide

3. The antiparkinsonian levodopa (L- dopa) is decarboxylated in the neuron to the active dopamine.

D. Sites of Metabolism/ Drug Biotransformation

Liver
- The enzymes involved in metabolism are present in
many tissues but generally are more concentrated
in the liver

- Enzymes located in the endoplasmic reticulum of

liver cells protect the organism against an
accumulation of lipid-soluble exogenous and
endogenous compounds by converting them to
water-soluble metabolites which can be easily
excreted by the kidney

- Cytochrome P450 enzyme species (eg, CYP2D6

and CYP3A4) that are responsible for much of drug
metabolism. Many isoforms of CYP have been
recognized

Prepared by: Aldrex B. Dacawe, RPh, MS Pharm

Lectured by: Mary Christine S. Cariño, RPh, MS Pharm Page 2 of 4

 Saint Louis University | Department of Pharmacy

Pharm 222: Pharmaceutical and Medicinal Organic Chemistry (Lecture)

Extrahepatic Metabolism
- Refers to drug biotransformation/ metabolism that takes place in tissues other than the liver

- The most common sites include the portals of entry & exit of excretion

- The extrahepatic sites are as follows:

1. Plasma
- Contains esterase enzymes which is responsible primarily for the hydrolysis of esters

- Example: Simple esters (procaine, succinylcholine)

- Additionally, plasma esterases can activate a variety of prodrugs

2. Intestinal mucosa
- Lipid- soluble drug passes through the intestinal mucosa

- Metabolized before entering the blood

- The result is comparable to first- pass effect

3. Intestinal bacterial flora

- Secrete a number of enzymes capable of metabolizing drugs & other xenobiotics

- Any factor that modifies the intestinal flora may also modify drug activity

- Intestinal bacterial flora secrete beta- glucuronidase enzyme

- Certain bacterial flora convert vitamin precursor to their active forms

- Bacterial flora can also convert certain substances to their toxic forms

- Intestinal flora produce azoreductase enzyme

4. Stomach
- Has acidic environment

- This acidic environment produces non- enzymatic degradation of some drug molecules

- Gastric acid assists in the degradation of CHONs & peptides

5. Nasal mucosa
- Provides a high level of CYP450

- Nasal decongestants, anesthetics, nicotine, cocaine

E. Cytochrome P450
- Cytochrome P450 (CYP450) enzymes are essential for the production of cholesterol, steroids, prostacyclins, and
thromboxane A2.

- They are mixed function oxidases that catalyze the vast majority of oxidation reactions

- They also are necessary for the detoxification of foreign chemicals and the metabolism of drugs.

- CYP450 enzymes are so named because they are bound to membranes within a cell (cyto) and contain a heme
pigment (chrome and P) that absorbs light at a wavelength of 450 nm when exposed to carbon monoxide.

- There are more than 50 CYP450 enzymes, but the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5
enzymes metabolize 90 percent of drugs.

- These enzymes are predominantly expressed in the liver, but they also occur in the small intestine (reducing drug
bioavailability), lungs, placenta, and kidneys.

Prepared by: Aldrex B. Dacawe, RPh, MS Pharm

Lectured by: Mary Christine S. Cariño, RPh, MS Pharm Page 3 of 4

 Saint Louis University | Department of Pharmacy

Pharm 222: Pharmaceutical and Medicinal Organic Chemistry (Lecture)

F. Enzyme Inhibition and Enzyme Induction

This is a type of drug interaction which occurs when two or more drugs are administered simultaneously.

The state of enzymatic systems involved in drug biotransformation represents an important factor in
pharmacokinetic and/ or pharmacodynamic variability. The changes in the state of enzymes for metabolism of
drugs may be qualitative and quantitative.

Qualitative changes are commonly due to impairments in the state of the enzymatic systems. Quantitative
changes may evolve in two directions: either (1) the stimulation of enzymatic activity (enzyme induction) or (2)
the reverse, a reduction in enzyme activity (enzyme inhibition).

• Precipitant Drug- the drug that causes change

• Object drug- the drug that undergoes change

Enzyme Inhibition
- The precipitant drug inhibits enzymes for object drug and so the object drug’s metabolism becomes slow.

- Example: Cimetidine + Theophylline

Enzyme Induction
- The precipitant drug induces enzymes responsible the metabolism of object drug and so the object drug’s
metabolism becomes fast.

- Example: Phenobarbital + Amoxicillin

Enzyme Inducers Enzyme Inhibitors

Phenobarbital
Metronidazole

Phenytoin
Erythromycin

Rifampicin
Disulfiram

Carbamazepine
Isoniazid

Chronic Alcohol Use

Cimetidine

Cigarette Smoking Ketoconazole

Acute Alcohol Use

Valproic acid

Grapefruit Juice

Omeprazole

Fluoroquinolones

End of lecture. Thank you for listening.

“Even if you started weak, try your hardest to finish strong.” -Dacawe, 2020

Prepared by: Aldrex B. Dacawe, RPh, MS Pharm

Lectured by: Mary Christine S. Cariño, RPh, MS Pharm Page 4 of 4