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Drug Metabolism

PHRM 6100

What is Metabolism or biotransformation? The conversion from one chemical form of a drug to another
Xenbiotic chemical compound foreign to living organism
Why is Metabolism important? because the many drugs after they did their certain "job" they flow in the body but need to be excreted. in order for these drugs to get excreted they need to be metabolized first
What is the primary organ for drug absorption? what are some secondary ones? Primary: liver .. Secondary: kidney, lungs, intestines, blood cells
Phase I of biotransformation Parent drug converted to a more polar metabolite by introducing unmasking function groups .. it has oxidation, reduction, hydrolysis .. products are often inactive (but not always)
Phase II biotransformation Conjugation of typically phase I products with endogenous substrates .. products are inactive and highly polar and readily excreted
What are some exceptions to Phase I and Phase II biotransformation Isoniazid (phase II before I) .. Morphine - Active glucuronide
Hepatic metabolism - Phase I reactions Reactions catalyzed by specific cellular enzymes .. may be located in the ER, mitochondria, cystosol, lysosomes, nuclear envelope or plasma membrane
What is an important class of enzymes in phase I reaction? Microsomal mixed function oxidases
What does the activity of Hepatic metabolism require? A reducing agent NADPH and molecular Oxygen
What would you find in the Microsomal fraction? what about the cytosolic fraction? Microsomal: CYP450s, NADPH, FMOs and UGTs .. Cytosolic: SULTs, GSTs, and NAT
What are the salient (noticeable) features of Microsomal oxidation reaction High lipid solubility .. Low substrate specificity: permits oxidation of large number of substrates .. Generally slower than conjugation reaction
What are some CYPS identified in the liver? CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, CYP3A4
What does P450 enzyme inducers do Increase rate of synthesis of metabolizing enzymes .. more enzyme more metabolism .. implication of active drug and active metabolites
What does P450 enzyme inhibitors do Block enzyme access to substrate .. different mechanism (competitive and noncompetitive) less access so less metabolism .. implications for active drugs and metabolites
What are the therapeutic implications of INDUCTION for Active drugs and active metabolites? Active drug --> Decreased efficacy due to rapid metabolism ....... Active metabolites --> Increased drug effect and/or toxicity due to enzyme inuction
what are the therapeutic implication of INHIBITION for active drug and active metabolite Active drug --> increased efficacy and/or toxicity due to reduced metabolism ....... Active metabolite ---> decreased drug effect due to enzyme inhibition.
what are some factors influencing drug metabolism? Genetic factors: polymorphism, individual differences .... Phyiologic factors: Age, sex, pregnancy .... Environmental factors: food, drink, enzyme inhibition/induction
What would be a reason to decrease blood flow to the liver? Cardiac failure
What would change drug metabolizing capacity? Hormonal disease, infections, and inflammation
What are some Nonmicrosomal oxidations? (occur outside the microsomes) Alcohol Dehydrogenases (ADH) .. Aldehyde Dehydrogenases (ALDH) ..... Aldo-ketoreductases (AKR) ...... Molybdenum Hydroxylases
What happens in Monoamine oxidase? ** Substrates are primary amines (and Secondary or tertiary amines) .. ** Amines must be attached to an unsubstituted methylene group .. **play a vital role in inactivating neurotransmitters.
What happens in Diamine Oxidase? Substrates are diamines .... Histamine - Prototypical substrate ..... Has affinity for monoamines as well (at higher concentrations)
Give a summary to Phase I reactions ** Phase I products can be substrates for subsequent phase II reactions (applicable for 2 and 4 from the answer) They introduce new polar functional groups into the molecules which leads to: 1. Decrease pharm. activity (deactivation) 2. Increase Pharm. activity (activation) 3. Increased toxicity (carcinogenesis, mutagensis, cytotoxicty) 4. Altered pharm. activity
What are the 5 most common conjugation reactions, in order how much they contribute to phase II reactions 1. Glucuronidation 2. Sulfation 3. Glutathione conjugation 4. Acetylation 5. Methylation
what do conjugation reactions do? They add a hydrophilic moiety to xenobiotics rendering them easily excreted (urine, bile)
TRUE/FALSE: Sequential conjugation of the same substrate can occur TRUE .. Also, pathways can compete for same functional groups.
what conjugate reaction occur in Phenolic OH? Sulfation, Glucuronidation, methylation
what conjugate reaction occur in Amine groups? Acetylation, sulfation, glucuronidation
What conjugate reactions occur in carboxyl groups? amino acids and coA conjugation, glucuronidation
Which conjugate reaction is the most important? Glucuronidation
What is the reaction mechanism of glucuronidation **** A high capacity, low affinity reaction .. Direct conjugation of acceptor moiety w/ glucuronic acid .. **catalyzed by UGT .. Resultant water soluble glucuronide .. not all glucuronides excreted in urine
Takmela lal kabel .. Endogenous substrates include: Catelcholamines, thyroxine, steroids, and bilirubin
Can glucuronides be active and or toxic? give an example They can be active or very toxic .. Morphine for examplenhas active glucuronide
What us sulfation (sulfonation) important for? important in the reaction in the biotranformation of steroid hormones, catecholamines, bile acids, thyroxine, phenolic drugs .. can reactivate electrophiles or therapeutically active conjugates
What is the mechanism of sulfation (sulfonation) **** Low capacity high affinity reaction .. involves transfer of sulfonic group (-SO3-) from 3'-phosphoadenosine-5'-phaphosulfate (PAPS) to the acceptor molecule - catalyzed by SULTs --> substrate selectivity differs...
Takmela lal kabel .. What determines the reaction rate in sulfation? availability of PAPs and inorganic substrate.
Created by: amiqnais