UNIVERSIDAD DE ZAMBOANGA

School of Allied Medicine (SAM)

Pharmacy Department
PHARM CHEM – 2 LABORATORY
PHARMACEUTICAL, ORGANIC MEDICINAL CHEMISTRY

Name: Jasher Dave C. Acabal and Nelil Sapal Course/Sec: BSPh- 3B Date Submitted: April 5, 2018
Group Name: Schedule: TThS (6:00-8:00 pm) Date Performed: April 5, 2018

Experiment No. 11
METABOLISM OF DRUGS

I. OBJECTIVE: To determined how the drugs are metabolized in the body

II. MATERIALS:
Textbook in Organic Medicinal and Pharmaceutical Chemistry.
Textbook Of Medicinal Chemistry. Volume 1 & 2 .
Remington: The Science and Practice of Pharmacy
Essentials of Pharmaceutical Chemistry
Remington: Essentials of Pharmaceutics. 1st Edition.
Review of Organic Functional Groups: Introduction to Medicinal Organic Chemistry.
Internet Surfing @ Legit Websites.

III. PROCEDURE:
Determine how the selected drugs are metabolized and give their respective metabolites.

IV. METABOLISM OF SELECTED DRUGS:

1. Digoxin
Pharmacologic Category: cardiac glycoside
Metabolism Only a small percentage (13%) of a dose of digoxin is metabolized in healthy
volunteers. The urinary metabolites, which include dihydrodigoxin, digoxigenin bisdigitoxoside, and
their glucuronide and sulfate conjugates are polar in nature and are postulated to be formed via
hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the
cytochrome P-450 system, and digoxin is not known to induce or inhibit thecytochrome P-
450 system.

2. Tolazamide
Pharmacologic Category: antidiabetic
Metabolism Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity
from 0% to 70%. They are excreted principally in the urine. Following a single oral dose of tritiated
tolazamide, 85% of the dose was excreted in the urine and 7% in the feces over a five day period.
Most of the urinary excretion of the drug occurred within the first 24 hours postadministration.

3. Norfloxacin
Pharmacologic Category: quinolone antibiotic
Metabolism Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion.
After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and
82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion
occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal
clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the
administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered
in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less
than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the
administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2)
approximately 22% of the administered dose was recovered in urine and renal clearance averaged
154 mL/min.
 4. Ethacrynic acid
Pharmacologic Category: loop diuretic
Metabolism: has little or no effect on glomerular filtration or on renal blood flow, except
Following pronounced reductions in plasma volume when associated with rapid diuresis. The
electrolyte excretion pattern of ethacrynic acid varies from that of the thiazides and mercurial
diuretics. Initial sodium and chloride excretion is usually substantial and chloride loss exceeds
that of sodium. With prolonged administration, chloride excretion declines, and potassium and
hydrogen ion excretion

5. Phentermine
Pharmacologic Category sympathomimetic – weight suppressant
Metabolism The literature reported cumulative urinary excretion of phentermine under uncontrolled
urinary pH conditions is 62% to 85%. Exposure increases can be expected in patients with renal
impairment. Use caution when administering phentermine to patients with renal impairment.

6. Paraldehyde
Pharmacologic Category: anticonvulsant, hypnotic and sedative
Metabolism: It undergo depolymerization to acetaldehyde followed by oxidation.

7. Diclofenac Sodium
Pharmacologic Category: non-steroidal anti-inflammatory drug
Metabolism: ive diclofenac metabolites have been identified in human plasma and urine. The
metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4', 5-dihydroxy- and 3'-hydroxy-4'-
methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak
pharmacologic activity. The formation of 4’-hydroxy-diclofenac is primarily mediated by CPY2C9.
Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by
biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8
may also play a role in diclofenac metabolism.

8. Colchicine
Pharmacologic Category: antigout
Metabolism: Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and
3-O-demethylcolchicine (2- and 3-DMC, respectively), and one minor metabolite, 10-O-
demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes
have shown that CYP3A4 is involved in the metabolism of colchicine to 2- and 3-DMC. Plasma
levels of these metabolites are minimal (less than 5% of parent drug)

9. Alprostadil
Pharmacologic Category: Prostaglandin
Metabolism: Alprostadil is rapidly converted to compounds which are further
metabolized prior to excretion. Following intravenous administration, approximately 80%
of circulating alprostadil is metabolized in one pass through the lungs, primarily by betand
omega-oxidation. Hence, any alprostadil entering the systemic circulation following
intracavernosal injection is very rapidly metabolized. Following intracavernosal injection of 20
micrograms alprostadil, peripheral levels of the major circulating metabolite, 13,14dihydro-15-
oxo-PGE1, increased to reach a peak 30 minutes after injection and returned to pre-dose levels
by 60 minutes after injection.

10. Megestrol
Pharmacologic Category: appetite stimulant - Progestin
Metabolism: Megestrol metabolites which were identified in urine constituted 5% to 8% of the
dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have
accounted for at least part of the radioactivity not found in urine and feces.
VIII. CONCLUSION:

It is important to determine how the selected drugs are metabolized and learn their respective
metabolites.

VIII. Q U E S T I O N S :

1. What is the organ mainly involved in drug metabolism?

Liver is the organ mainly involved in drug metabolism.

2. What are the Different Factors that affect Drug Metabolism?

1. Sex differences 6.Tolerance

2. Strain differences 7. Body Surface Height/ wieght
3. Genetic factors 8. Pregnancy
4. Enzyme Inhibition 9. Vitamins and minerals
5. Enzyme Induction 10. Starvation

3. What is the IMPORTANCE of Cytochrome- P450 in Drug Metabolism?

Cytochrome P450 is the major drug-metabolizing enzyme system, playing a key role in
detoxification and toxification, and is of additional significance in medicinal chemistry
because several CYP enzymes are drug targets, for example, thromboxane synthase
(CYP5) and aromatase (CYP19). The three CYP families mostly involved in xenobiotic
metabolism are CYP1 to CYP3.

4. What are The PRINCIPLES involved in Drug Metabolism?

The metabolism of drugs and other xenobiotics is often a biphasic process in which the
compound may first undergo a functionalization reaction (phase I reaction) of oxidation,
reduction, or hydrolysis. This introduces or unveils a functional group such as a hydroxy or
amino group suitable for coupling with an endogenous molecule or moiety in a second
metabolic step known as a conjugation reaction (phase II reaction) [19,24]. In a number of
cases, phase I metabolites may be excreted prior to conjugation, while many xenobiotics
can be directly conjugated. Furthermore, reactions of functionalization may follow some
reactions of conjugation, for example, some conjugates are hydrolyzed and/or oxidized
prior to their excretion.

5. Do metabolites produced have the same pharmacologic activity as the Principal

Drug? If YES, WHY? If NO, WHY NOT? EXPLAIN.

Metabolism represents the most prevalent mechanism for drug clearance. Many drugs are
converted to metabolites that can retain the intrinsic affinity of the parent drug for the
pharmacological target. Drug metabolism redox reactions such as heteroatom
dealkylations, hydroxylations, heteroatom oxygenations, reductions, and dehydrogenations
can yield active metabolites, and in rare cases even conjugation reactions can yield an
active metabolite. To understand the contribution of an active metabolite to efficacy relative
to the contribution of the parent drug, the target affinity, functional activity, plasma protein
binding, membrane permeability, and pharmacokinetics of the active metabolite and parent
drug must be known.
Reference:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/02177
http://files.chuv.ch/internet-docs/pha/recherche/cb_2010_burger7_metabolism.pdf
https://www.wikidoc.org/index.php/Colchicine
www.drugbank.ca/drugs/DB09117