Chapter 13. Drug Metabolism

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Chapter 13. Drug Metabolism

• Introduction the process of drugs in the body
  includes absorption, distribution, metabolism and
  elimination. Drug metabolism is also named drug
  biotransformation

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• Important Terms
• Biotransformation Processes of drugs or toxins
  in the body, which may change the physical,
  chemical or biological properties of the drugs or
  toxins.
• Bioavailability F, the fraction of the dose
  that reaches the systemic circulation. F1 for IV
  administration.
• Distribution Movement of drug from the central
  compartment (tissues) to peripheral compartments
  (tissues) where the drug is present.

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• Elimination The processes that encompass the
  effective "removal" of drug from "the body"
  through excretion or metabolism.
• Half-Life the length of time necessary to
  eliminate 50 of the remaining amount of drug
  present in the body.

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Routes of Administration

• Oral
• Injection Intravenous, Subcutaneous,
  Intramuscular, Intraperitoneal
• Transdermal (patch)
• Mucous membranes of mouth or nose (includes
• nasal sprays)
• Inhalation
• Rectal or vaginal

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1. Biotransformation and the enzymes

• The major site for drug biotransformation is the
  liver. The extrahepatic sites include the lung,
  kidney, intestine, brain, skin, etc.
• The major organelles for drug biotransformation
  is microsome, and others include cytosol and
  mitochondria.
• The major enzymes for drug biotransformation are
  microsomal enzymes.

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Drug Metabolism
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic microsomal enzymes (oxidation,
conjugation)
Hepatic non-microsomal enzymes (acetylation,
sulfation,GSH, alcohol/aldehyde
dehydrogenase, hydrolysis, ox/red)
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Reactions in biotransformation

• Include Phase 1 Phase 2 Reactions.
• Phase 1 involves metabolic oxygenation,
  reduction, or hydrolysis result in changes in
  biological activity (increased or decreased)
• Phase 2 conjugationbound by polar molecules or
  modified by functional groups, in almost all
  cases results in detoxication.

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1) The first phase reactions

• Metabolic oxygenation
• Microsomal enzymes catalyze hydroxylation,
  dealkylation, deamination, S-oxidation,
  N-oxidation and hydroxylation, dehalogenation,
  etc.

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a) Hydroxylation Hydroxylations include
aliphatic and aromatic hydroxylation
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b) Dealkylation

• Dealkylations include N-, O- and S-dealkylation.
• R-X-CH2-R
• R-X-CH(OH)-R
• R-XH OCH-R

O
X O, N, S
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N-dealkylation

• Dealkylation of secondary or tertiary amines will
  produce primary amines and aldehydes.

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O-dealkylation

• Dealkylation of ethers or esters will produce
  phenols and aldehydes.

Codeine
Morphine
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S-dealkylation

• S-dealkylation usually produces sulfhydryl group
  and aldehyde.
• R-S-CH3 R-S-CH2OH R-SH
  HCHO

O
6-methylthiopurine 6-thiopurine
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c) Deamination

• Deamination may produce ketone and ammonia.

For example, deamination of amphetamine
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d) S-oxidation
For example, S-oxidation of chlorpromazine
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e) N-oxidation
For example, N-oxidation of chlorpheniramine
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• B. Microsomal oxidases and their action
  mechanisms
• The enzymes that catalyze the above oxygenation
  of drugs are called mixed- function oxidase or
  monooxygenase. In the reactions, one oxygen is
  reduced into water and the other is integrated
  into the substrate molecule.
• RH O2 NADPH H ROH NADP H2O

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• Mixed-function oxidase contains cytochrome P450
  (CYP) and NADPH as electron carrier and hydrogen
  provider.
• The CYP family Human CYPs have several types
  and subtypes, named CYP1, 2, 3 CYP1a, 1b, and
  so on. They are important in drug metabolism.

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Human Liver CYPs
S. Rendic F.J. DiCarlo, Drug Metab Rev
29413-80, 1997
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• C. Other oxidases
• Monoamine oxidase
• These enzymes exist in mitochondria.
• They catalyze oxidation of amines into aldehyde
  and ammonia. For example, degradation of
  5-hydroxytryptamine.
• RCH2-NH2 RCHNH RCHO NH3

O
H2O
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• Alcohol and aldehyde oxidases
• R-CHOH R-CHO R-COOH

Alcohol dehydrogenase
Aldehyde dehydrogenase
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D. Reductions

• Aldehyde and ketone reductases these enzymes
  catalyze reduction of ketones or aldehydes to
  alcohols.
• For example
• CCl3CHO CCl3CH2OH
• The coenzyme may be NADH or NADPH.

2H
Trichloroacetaldehyde
Trichloroethanol
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• Reductases for Azo or nitro compounds
• These reductases mainly exist in hepatic
  mitochondria with NADH or NADPH as coenzyme.

Azo
Aniline
Nitrobenzene
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E. Hydrolysis

• Esters and amides may be hydrolyzed to produce
  acids and alcohol or amine.

Para-aminobenzoic acid
Ester(Procain)
Amide(Procainamide)
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2) The second phase reactions

• The second phase reactions of drugs are also
  named Conjugation Reactions . These reactions
  include glucuronidation, sulfation, acetylation,
  methylation and amino acid binding.

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Glucuronidation
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SulfationPAPS is the phosphate donor.
(PAPS, 3-phosphoadenosine- 5-phosphosulfate)
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Acetylation
Acetylation may reduce the water solubility of
the compounds.
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Methylation

• Methylation of phenols, amines and biologically
  active molecules may change their activity or
  toxicity. Generally, methylation reduces the
  hydrophilicity of the compound.
• S-adenosylmethionine (SAM) is the donor of
  methyl group.
• Methylation includes N- or O-methylation.

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• Methylation
• RH R-CH3

SAM
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2. Factors that affect drug metabolism

• Inducers
• Inducers are those that promote drug metabolism
  in the body. Most inducers are lipophilic
  compounds and have no specificity in actions.
• Examples barbital, ether, amidopyrine, miltown
  (meprobamate), glucocorticoids, vit. C, etc.
  Repeated administration of these drugs may result
  in drug-resistance.

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• The mechanism by which inducers enhance drug
  metabolism in the body is believed to be the
  induction of the enzymes involved in the drug
  metabolism.
• For example, phenobarbital stimulates
  proliferation of SER and increases production of
  some enzymes in the metabolisn of drugs, such as
  liver CYPs and UDP-glucuronate transferase, both
  of which enhance metabolism of many drugs in the
  liver (oxygenation and conjugation).

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• Inhibitors
• Inhibitors are those that inhibit drug metabolism
  in the body. Include competitive and
  non-competitive inhibitors.
• a) A drug inhibits the metabolism of other drugs
  such as chloramphenicol and isoniazid. They
  inhibit hepatic microsomal enzymes. Combined
  administration of these drugs and others such as
  barbitals may increase the toxicity of the
  latter.

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• b) Non-drug compounds inhibit the metabolism of
  drugs such as pyrogallol (????). This compound
  inhibits o-methylation of epinephrine and thus
  enhances the activity of the hormone in body (it
  competes with epinephrine for methyltransferase).

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• Other factors
• Species difference.
• Sex, age, nutrition conditions have effects on
  drug metabolism.
• Hepatic functions.

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3. Significance of drug biotransformation

1. Effective removal of drug from the body through
   excretion or metabolism. For example, sulfation
   and glucuronidation increase secretion of the
   drug in urine.
2. Change of the biological activity or toxicity of
   drugs in the body. For example,
   trichloroacetaldehyde is first reduced into
   trichloroethanol and then conjugated by
   glucuronate to become a non-toxic compound.

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1. Inactivation of bioactive molecules in the body.
   For example, some hormones are inactivated
   through biotransformation in the liver
   (epinephrine, steroid hormones).
2. Exploration of new drugs. Based on the mechanisms
   of biotransformation, it is possible to design
   new drugs with longer half-lives and fewer
   side-effects.
3. Explanation for the carcinogenic property of some
   drugs. For example, after biotransformation some
   non-toxic drugs may become toxic or
   carcinogenic.

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N-acetylation may form nitrenium ion which is a
potent carcinogenic agent
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• The mechanisms of biotransformation may be used
  to improve the efficacy of drugs. For example,
  those that are mainly metabolized in the liver
  may have less efficacy through oral
  administration than IV route.