SAS 3 Introduction to Drug Metabolism and Phase I Metabolism Reactions Flashcards
Plays a central role in the elimination of drugs and other foreign compounds (xenobiotics) from the body.
METABOLISM
Most organic compounds entering the body are
lipophilic.
If lipophilic drugs were not metabolized to polar, water- soluble products, they would remain
indefinitely in the body, eliciting their biologic effects.
The formation of water- soluble metabolites not only enhances DRUG ELIMINATION, but also leads to compounds that are generally pharmacologically
INACTIVE and relatively NONTOXIC.
Drug metabolism reactions are regarded as
detoxication (or detoxification) processes
Prodrugs
parent compound is inactive when administered & must be metabolically converted to a biologically active drug (metabolite).
it is now clear that not all metabolites are
nontoxic
is the process of preparing foreign chemicals for removal from the body
Metabolism
is usually terminated by metabolic processes
Drug action
is one factor in determining the duration of drug action
The rate of drug metabolism
Metabolism often occurs in two step10 s
Phase I (FUNCTIONALIZATION)
Phase II (CONJUGATION)
Phase I
Functionalization phase
involves chemical transformations, usually catalyzed by enzymes, including oxidations, reductions, hydrolyses, and other reactions that prepare the drug for elimination from the body.
Phase I metabolism
generally found in the ER
Oxidative enzymes
Hydrolytic enzymes
most often located in the cell cytoplasm or in plasma
Conjugation enzymes
cytoplasm & ER
PHASE 1 POLAR FUNCTIONAL GROUP
(OH, COOH, NH2, SH)
Direct introduction of functional group or by modifying or _____ existing functionalities (e.g., reduction of ketones and aldehydes to alcohols; oxidation of alcohols to acids; hydrolysis of esters and amides to yield COOH, NH2,OH groups)
“unmasking”
Phase I. An Analogy
Drug Molecule + Functional Group + More Polar than the Drug molecule
metabolism are more polar than the drug molecule.
PHASE I
Although, Phase 1 may not produce sufficiently hydrophilic or inactive metabolites, they generally tend to provide a _________ in the molecule that can undergo subsequent Phase II reactions.
functional group or “handle”
to attach small, polar, and ionizable endogenous compounds such as glucuronic acid, sulfate, glycine and other amino acids to the functional handles of Phase I metabolites to form WATER- SOLUBLE CONJUGATED PRODUCTS.
Phase II
Phase II. An Analogy
More polar than the drug molecule + small, polar, and ionizable endogenous compounds such as glucuronic acid, sulfate, glycine and other amino acids = WATER- SOLUBLE CONJUGATED
PRODUCTS
Complement one another in detoxifying and facilitating the elimination of drugs and xenobiotics.
Phase I and Phase II reactions
- most important organ in drug metabolism.
- Rich in almost all of the drug- metabolizing enzymes
Liver
A well- perfused organ and plays a paramount role in the detoxification and metabolism of endogenous and exogenous compounds in the bloodstream.
Liver
Drugs administered orally and are absorbed through the GI tract must first pass through the LIVER (therefore, they are susceptible to hepatic metabolism—__________ ) before reaching the systemic circulation
first- pass effect
Examples of drugs undergoing first- pass effect
Salicylamide
Lidocaine
Isoproterenol
Meperidine
Pentazocine
Propoxyphene
Propranolol
Morphine
Nitroglycerine
Reaction requires both molecular oxygen and the reducing agent NADPH (nicotinamide adenine dinucleotide phosphate).
OXIDATIVE BIOTRANSFORMATION PROCESSES
Most common and important in drug metabolism
RH + NADPH + O2 + H+ —->ROH + NADP+ + H2O
Most common and important in drug metabolism
RH + NADPH + O2 + H+ —->ROH + NADP+ + H2O
