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xenobiotic
any foreign compound as opposed to an endogenous compound (hormone, glucose, steroid etc). most drugs are xenobiotics unless they are replacements like hormones, glucose, steroids etc TERM 2
Biotransformation
DEFINITION 2 Biotransformation is required to make bioactive compounds more watersoluble. This is required because the major route of elimination of drugs is the kidney which requires a water soluble compound (urine is water). Note that the term biotransformation is preferred to metabolism. TERM 3
Biotransformation of a Drug
DEFINITION 3 Biotransformation of a Drug A can lead to metabolites of Drug A that are: (a) inactive AND/OR (b) active AND/OR (c) toxic (most likely never FDA approved if the drug is converted bythe body into a toxic metabolite)Liver is the site of most biotransformation. Yes, other tissues will perform biotransformations, but liver is the most important for most drugs. TERM 4
biotransformation reactions
DEFINITION 4 All biotransformation reactions of drugs can be divided up into Phase I and Phase II. (a) Phase I can occur before Phase II (b) Phase I can occur after Phase II (c) Phase I can never occur, only Phase II (d) Phase II can never occur, only Phase I TERM 5
Phase I reactions
DEFINITION 5 Phase I reactions make drug more polar by unmasking or adding a functionalgroup on the drug (OH, NH2, SH etc etc). Phase I metabolites are more water-soluble.
Phase II
reactions
Phase II reactions are conjugation reactions. A glucuronic acid, sulfuric acid, acetic acid, amino acid etc etc is ADDED to the drug molecule. Remember that this addition can occur after Phase I or before Phase I Phase II metabolites are highly water soluble. Isoniazid (an anti-TB drug) undergoes Phase II and then a Phase I. See Fig 4-2, pg 54 TERM 7
First-Pass effect
DEFINITION 7 (a) Swallow pill (b) Pill dissolves in the stomach (called the dissolution rate) (c) Dissolved pill arrives in the duodenum (d) Absorption into the central compartment begins (e) Portal vein (check anatomy book) delivers blood to the liver for thefirst pass through the liver. (f) During first pass through the liver X % of the drug is biotransformed. If the amount lost to biotransformation is 2% of the dose, no problem. If the amount is say 90%, then the drug is lost. No therapeutic benefit to giving the drug. TERM 8
First Pass effect -example
DEFINITION 8 (g) Example worth remembering: lidocaine, always given iv because of very high amount lost during first pass through the liver. (h) Ways to reduce first pass effect: avoid the portal veins. Examples, patch, rectal (poor but useful), vaginal, sublingual, iv, sc, etc. (I) Deja Review, pg 4 (just a suggestion). TERM 9
Phase I, so what does that
mean?
DEFINITION 9 It is the name of the family of enzymes found in the liver that do Phase I reactions. These enzymes are foundin microsomes in the ER (endoplasmic reticulum). Phase I found on smooth ERmicrosomes = artificial term used to describe what you end up with in the bottom of a test tube after you mash upthe liver and centrifuge the tube. Phase II = enzymes found in the cytosol compared toPhase I enzymes found on membranes (microsomes) TERM 10
Phase 1, what does this mean continued
DEFINITION 10 The enzymes that do Phase I reactions on smooth ER (no ribosomes) are called mixed function oxidases (MFOs) or monooxygenases
Suicide Inhibitors
A special category of inhibitors. In most cases the drug that inhibits orinduces stops its influence when that drug is stopped. Suicide inhibitorscause irreversible damage to the CYP enzyme TERM 17
Phase II
Reactions
DEFINITION 17 Called coupling or conjugation reactions (see why in above) See Table 4-3 for a list of examples. Most (but not all) of the enzymes are in the cytosol TERM 18
Biotransformtion to a Toxic Metabolite
DEFINITION 18 The liver has no brain. It does what it does without regard to what it ismaking from a drug. Sometimes what it makes (biotransforms) is toxic. Acetaminphen.Fig 4-5, Pg 61 in Katzung. Important. Great exam question(s). GTQ (good test question) Acetaminophen is biotransformed by Phase II conjugation by being linkedthrough glucuronidation which requires GSH. When GSH is depleted dueto poor nutrition or acetaminophen overdose the liver forms toxic metabolite which destroys liver cells. Liver transplant required or patient dies.Antidote: N-acetylcysteine replaces GSH.
