3 Medical Mathematics: Drug Metabolism (biotransformation) Flashcards
What are the Results of biotransformation?
Change in physicochemical properties of the drug
• The metabolite is more water soluble, polar, and ionized
Change in pharmacological activity
• Bioinactivation or detoxification (most drugs)
• Bioactivation or lethal synthesis (few drugs)
What are Examples of biotransformation?
Active drug (aspirin) to active metabolite (salicylic acid) Inactive drug (chloral hydrate) to active metabolite (trichloroethanol) Nontoxic drug (parathion) to toxic metabolite (paroxon)
What are Sites of biotransformation?
Liver
• Smooth endoplasmic reticulum (microsomes)
• Hepatocyte cytoplasm, mitochondria, lysosomes, nuclear envelope, plasma membrane
Other tissues (the nervous tissue, kidney, GI tract, lungs, and skin)
Plasma
Hepatic Metabolism
Enzymes lack specificity (e.g., Cytochrome P450, CYP450 “MFO”)
Enzymatic reactions are saturable reactions
Drugs can compete on the same enzyme
Enzymes can be induced or inhibited by drugs
Microsomal enzymes cause oxidation, reduction, hydrolysis and conjugation to glucuronic acid
Types of metabolic reactions
Phase I reactions (Oxidation, Reduction, and Hydrolysis)
Phase II reactions (synthetic) (Conjugation)
Phase I reactions (nonsynthetic)
• Oxidation
Microsomal (hydroxylation, deamination, dealkylation, desulfuration, sulfoxide formation)
Nonmicrosomal (cytosol or mitochondria)
Alcohol and aldehyde dehydrogenase (e.g., ethanol to acetaldehyde)
Xanthine oxidase (e.g., xanthine to uric acid)
Tyrosine hydroxylase (e.g., tyrosine to dopa)
Monoamine oxidase (e.g. metabolism of catecholamines and serotonin)
Oxidation is the most common biotransformation reaction
Phase I reactions (nonsynthetic)
• Reduction
Microsomal (e.g., nitro reduction of chloramphenciol)
Nonmicrosomal (e.g., aldehyde reduction of chloral hydrate)
Phase I reactions (nonsynthetic)
• Hydrolysis
Microsomal hydrolases
Nonmicrosomal hydrolases
» Esterases (e.g., acetylcholine, succinylcholine, procaine) » Amidases (e.g., procainamide)
» Peptidases (e.g., proinsulin)
Metabolites of phase I reactions are…
more or less water soluble, inactive, less active, or more active
Phase II reactions (conjugation)
Combination of a drug or its metabolite with an endogenous substance.
Occur with foreign compounds and endogenous chemicals.
Conjugation is to glucuronic acid, sulfuric acid, acetyl group, methyl group, glycine,
methionine and glutathione.
Conjugation to glucuronic acid is the most common conjugation reaction.
Glucuronidation is microsomal but all other conjugations are nonmicrosomal.
Conjugation is deficient in the neonate.
Metabolite conjugates are usually inactive and water-soluble.
Certain conjugation reactions may lead to formation of metabolites (acyl
glucuronidation of NSAID) that are hepatotoxic.
What Factors alter biotransformation?
Species Individual Route of administration Enzyme inducers Enzyme inhibitors Liver disease Hepatic blood flow Plasma protein binding Distribution and storage Age Sex Diet and nutrition Body temperature Environmental factors
Describe Species as a factor affecting biotransformation
Cats are deficient in glucuronyl transferases for phenols and aromatic amines but they may be able to conjugate endogenous substrates such as steroids, thyroxine, and bilirubin.
Cats also are deficient in hydroxylation and dealkylation.
Dogs lack acetylating enzymes.
Ruminants have less plasma pseudocholinesterase than horses, dogs and cats.
Ruminants and horses have high levels of oxidative enzymes.
Pigs are deficient in sulfate conjugating enzymes.
Birds lack oxidative enzymes.
Fish have low levels of drug metabolizing enzymes.
Describe Individual as a factor affecting biotransformation
Certain individuals may by deficient or lack certain enzymes due to genetic differences
Describe Route of administration as a factor affecting biotransformation
First-pass effect for oral and intraperitoneal routes (and drugs administered through the
skin)
Lidocaine, propranolol and morphine are examples of extensive first-pass effect
Describe Enzyme inducers as a factor affecting biotransformation
Drugs that stimulate the liver to produce more metabolic enzymes.
Only microsomal enzymes are inducible by drugs.
Examples are phenobarbital, phenylbutazone, griseofulvin, rifampin and chlorinated hydrocarbon insecticides.
Enzyme induction is reversible.
Enzyme induction may lead to tolerance or drug-drug interactions.
