Drug Metabolism, Pharmacogenetics, And Therapeutic Choice Flashcards
The first major route in which drugs are eliminated from the body is
Excretion through the Kidney (unchanged)
Plays a pivotal role in terminating the biological activity of some drugs, particularly those that have small molecular sizes or possess polar characteristics
Renal excretion
A property of most drugs that facilitates passage through biological membranes as well as access to sites of action is that most drugs are
Lipophilic
Renal excretion of lipophilic compounds is
Poor
The 2nd major route of drug elimination from the body is
Biotransformation of Drugs or Xenobiotics into more hydrophilic metabolites
Biotransformation of drugs to polar and hence more readily excretable products
Drug Metabolism
Alters the pharmacodynamic and pharmacokinetic properties of a drug, as well as the toxic properties
Drug Metabolism
Typically increases clearance and shortens half-lives to significant extents
Drug Metabolism
For example, the half-lives of lipophilic barbiturates (e.g., pentobarbital) would be extremely long if it were not for their metabolic conversion to
Water soluble compounds
Usually detoxifies, although some metabolic products have enhanced toxicity relative to the parent drug
Drug Metabolism
Most metabolic reactions occur at some point between absorption of the drug into the general circulation and its
Renal Elimination
In general, all of these chemical reactions can be assigned to one of two major categories, termed
Phase I and Phase II reactions
Introduce or expose a polar functional group (e.g., OH, COOH, NH2, or SH) on the parent compound
Phase I reactions
Typically involve the conjugation of endogenous compounds (e.g., glucuronic acid or glutathione) to phase I products to yield highly polar (but chemically inactive) conjugates
Phase II (Conjugation) Reactions
The principle organ of drug metabolic activity
Liver
Following oral administration, drugs are first transported via the portal system to the
Liver
This limits the oral bioavailability of highly metabolized
Drugs
In the GI tract, drugs may be metabolized by microorganisms, digestive enzymes, and
Gastric fluids
Major enzymatic system for Phase I functionalization (oxidative) reactions
Cytochrome P450 system
Promiscuous enzymes, with low substrate specificity
CYPs
The only common structural feature of the wide variety of drugs and chemicals that serve as substrates in the P450 system
High lipid solubility
For the CYPs, distinct gene families are designated by
Arabic numerals, ex: CYP3
Subfamilies are then designated by
Capital letters. Ex: CYP3A
Then individual genes are designated by a
Number. Ex: CYP3A4
These six enzymes are responsible for the bulk of the drug and xenobiotic metabolism in the liver
CYP3A4, 2C9, 1A2, 2E1, 2D6, and 2C19
Accounts for the metabolism of >50% of the clinically prescribed drugs that undergo hepatic metabolism
CYP3A4
Catalyze the coupling of an activated endogenous substance with an exogenous agent (e.g., a drug) or another endogenous compound
Transferases
Conjugation reactions require
Transferases
What are the 5 conjugation reactions?
Glucuronidation, N-Acetylation, Glutathione conjugation, Sulfation, and Methylation
Is quantitatively the most important conjugation reaction
Glucuronidation
What is the enzyme for glucuronidation?
UDP-glucuronosyltransferase (UGT)
Conjugation of reactive electrophilic compounds with the tripeptide glutathione (GSH)
-A major detoxification pathway for drugs and carcinogens
Glutathione conjugation
What is the enzyme for Glutathione conjugation?
glutathione-S-transferase (GST)
Drug metabolism reactions often occur sequentially (i.e., Phase I → Phase II). An exception to this is
Isoniazid (INH)
Genetic factors contribute to large inter-individual differences in
Metabolic Rate
What is the underlying mechanism for slower acetylators?
Polymorphism of NAT2 (N-Acetyltransferase 2) Gene
Inhibits CYP3A4 and decreases metabolism rates of some drugs
Grapefruit Juice
Exposure to drugs or xenobiotics can induce
Metabolizing enzymes
Many inducers of CYPs also induce enzymes involved in
Phase II reactions
Acute and chronic diseases that affect liver function or architecture markedly diminish
Drug metabolism
Can limit blood flow to the liver and impair the disposition of drugs (e.g., morphine and lidocaine) whose metabolism is flow-limited
Cardiac Disease
Can impair hepatic drug metabolism by impairing the activity or causing defective formation of metabolic enzymes
Heavy metal poisoning and Porphyria
