Pharmacokinetics for Nursing Pharmacology: Drug Metabolism

Nursing Pharmacology Chapter 2: General Principles: Pharmacokinetics

**Some Phase II Reactions**
Type of Conjugation	Endogenous Reactant	Transferase (Location)	Types of Substrates	*Examples*
Glucuronidation	UDP glucuronic acid	UDP glucuronosyl transferase (microsomal)	phenols, alcohols, carboxylic acids, hydroxylamines, sulfonamides	morphine, acetaminophen, diazepam, digitoxin, digoxin, meprobamate
Acetylation	Acetyl-CoA	N-Acetyl transferase (cytosol)	Amines	sulfonamides, isoniazid, clonazepam, dapsone, mescaline
Glutathione conjugation	glutathione	GSH-S-transferase (cytosolic, microsomes)	epoxides, nitro groups, hydroxylamines	ethycrinic acid, bromobenzene
Sulfate conjugation	Phosphoadenosyl phosphosulfate	Sulfotransferase (cytosol)	phenols, alcohols, aromatic amines	estrone, 3-hydroxy coumarin, acetaminophen, methyldopa
Methylation	S-Adenosyl-methionine	transmethylases (cytosol)	catecholamines, phenols, amines, histamine	dopamine, epinephrine, histamine, thiouracil, pyridine

Adapted from Table 4-3, Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 57.

Overview: Phase II reactions involve non-microsomal enzymes that metabolize drugs into forms that are easier for the body to eliminate.
- Reaction types:
  1. Conjugation
  2. Hydrolysis
  3. Oxidation
  4. Reduction
- Non-microsomal enzymes are mainly located in the liver (hepatic) but are also found in the plasma and gastrointestinal tract
- Non-microsomal enzymes catalyze all conjugation reactions except glucuronidation
Nonspecific esterase enzymes in liver, plasma, gastrointestinal tract hydrolyzed drugs that contain ester linkages. Examples of such drugs include succinylcholine (Anectine), Atricurium (Tracrium), Mivacurium (Mivacron), esmolol (Brevibloc) as well as "ester-type" local anesthetics.
Conjugation reactions are usually "detoxification reaction".
- Conjugates tend to be more polar compared to the parent compound, more easily excreted, and usually pharmacologically inactive.
  - Conjugation reactions require "high-energy" intermediates in specific transfer enzymes which include both microsomal and cytosolic transferases.
  - Conjugation with glucuronic acid:
- Transferases are enzymes which catalyzes the coupling of an endogenous substance with the drug.
  - For example, transferase which catalyzes the "transfer" of uridine-5'-diphosphate (UDP) derivative of glucuronic acid and a drug.
Toxicity:
- Certain conjugation reactions form toxic reactive species (hepatotoxicity).
  - For example, acyl glucuronidation of nonsteroidal anti-inflammatory drugs may result in toxicity.
    - Another example would be N-acetylation of isoniazid.
- Drugs metabolized to toxic products:
  - Acetaminophen hepatotoxicity. Acetaminophen (Tylenol) is normally safe in therapeutic doses.
  - At acetaminophen therapeutic doses:
    - Glucuronidation + sulfation to conjugates account for 95% of excreted metabolites with another 5% due to an alternative cytochrome P450 depending glutathione (GSH) conjugation pathway.
  - At high (toxic) acetaminophen doses:
    - The glucuronidation and sulfation pathways become saturated and do not have sufficient detoxification capacity.
    - Cytochrome P450 dependent pathway becomes now more important.
      - With depletion of hepatic glutathione, hepatotoxic (toxic to the liver), reactive, electrophilic metabolites are formed.
        
        In this circumstance antidotes would include N-acetylcysteine and cysteamine.
        
        N-acetylcysteine protects patients from fulminant hepatotoxicity and death following acetaminophen overdose.

References
Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp. 3-27 Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 50-61. Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.