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Drug Metabolism & Delivery Flashcards

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1
Q

Drug Metabolism

A
  • most metabolic products are less pharmacologically active
  • different metabolites have different effects
  • drug metabolism usually involves pathways for the biosynthesis of endogenous substrates
  • liver is major site of drug metabolism
  • drug metabolism required to convert lipophilic compounds into hydrophilic compounds to be excreted
  • if lipid soluble non polar compounds are not metabolised they remain in tissued and their effects are stronger
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2
Q

Types of drugs and metabolism

A
  1. hydrophilic drug: renal excretion
  2. lipophilic drug no metabolism: excretion impossible
  3. lipophilic drug: conversion in liver to hydrophilic metabolite
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3
Q

Pharmacokinetics

A
  • absorbed, metabolised, distributed, and eliminated

- needs to be considered during drug design process

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4
Q

Drug Dosage

A
  • influenced by pharmacokinetics
  • physical and chemical properties of a drug determine its success to reach its target
  • consider: bioavailability, metabolic stability, chemical stability
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5
Q

Phases of Metabolism

A

Phase 1: modification to hydrophilic compound

Phase 2: conjugation with large molecules for secretion

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6
Q

Phase 1 Transformation

A
  • introduce or unmask a functional group by hydrolysis or oxygenation
  • metabolites afterwards are inactive and can be excreted
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7
Q

Phase 2 Transformation

A
  • generate highly polar derivatives for excretion

- addition of glucoronide, sulfate, acetate, amino acids

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8
Q

Phase 1 Metabolism

A

Oxidation

  • addition of oxygen or removal of hydrogen
  • occurs in liver where oxidation takes place by cytochrome P450
  • oxidised products are more polar and water soluble

Reduction

  • removal of oxygen or addition of hydrogen
  • less common
  • uses cytochrome P450 or reductase enzymes

Hydrolysis

  • reaction between compound and water to give polar metabolite
  • uses amidase or esterase enzymes
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9
Q

Types of oxidation

A
  1. hydroxylation: addition of hydroxyl group
  2. N dealkylation: removal of methyl to give amine
  3. O dealkylation: removal of methyl to give alcohol
  4. deamination: removal of amino to give carbonyl
  5. N oxidation: addition of oxygen to amine to give amide
  6. S oxidation: addition of oxygen to sulfate
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10
Q

Types of Reduction

A
  1. nitro reduction to amine/hydroxylamine
  2. carbonyl reduction to alcohol (ketone or aldehyde to alcohol)
    - opposite of oxidation reactions
    - cytochrome 450 enzymes working in opposite direction
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11
Q

Types of Hydrolysis

A
  • ester or amide to acid and alcohol or amine
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12
Q

Phase One Mixed Function Oxidase

A
  • mixed function oxidase system is cytochrome P450 dependent
  • oxygen and reducing system (NAPDH) required
  • one atom of oxygen transferred to substrate and other undergoes two electron reduction and is converted to water
  • found in ER of different tissues
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13
Q

Cytochrome P450

A
  • catalyses hydroxylation or epoxidation of substrates
  • requires NADPH-cytochrom P450 reductase: flavoenzyme with one molecule of FAD and FMN
  • coenzyme transfers electrons for oxygen reduction in P450
  • membrane associated
  • contains heme : iron cofactor
  • molecule oxygen binds heme cofactor after reduction of Fe3+ to Fe2+ and is converted to reactive form
  • reactive form used for oxygenation reactions
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14
Q

P450 Structure

A
  • promiscuous enzyme
  • large binding active site
  • narrow binding for molecular oxygen on heme face
  • heme coordinated by Cysteine residues
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15
Q

Iron-Oxo Species

A
  1. free form enzyme: ferric heme with water occupying the oxygen binding site
  2. substrate binding
  3. acceptance of electrons from reductase to reduce the iron
  4. molecular oxygen binds to heme forming ferrous oxy species
  5. electron acceptance from reductase to form ferric peroxy species (TS)
  6. pick up proton from water to form ferric hydro-peroxy species
  7. second hydrogen released water from compound
  8. activated compound formed with free radical in ferryl oxo species capable of attacking the bound substrate
  9. transfer activated oxygen to the substrate (oxidation)
  10. water displaces substrate to regenerate active site
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16
Q

What happens if substrate binding to P450 is unfavorable ?

A
  • mechanisms are present to see if the interaction is favoured
  • if not the ferrous oxy species falls back to ferric heme and oxygen is dissociated
  • ferryl oxo and ferric hydroperoxo species can also fall back without substrate modification
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17
Q

Order of Iron-Oxo species

A
  1. ferric heme
  2. ferrous heme
  3. ferrous oxy
  4. ferric peroxy
  5. ferric hydroperoxo
  6. ferryl oxo
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18
Q

Phase 2 Transformations

A
  • when phase 1 products are not sufficiently hydrophilic or inactive to be eliminated the metabolites undergo phase 2
  • phase 2 modifies functional groups by a conjugation reaction
  • conjugate large polar molecules to water soluble products
  • requires a coenzyme
  • catalysed by transferases
  • conjugates unable to cross membranes and are therefore biologically inactive
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19
Q

Types of Phase 2 Conjugations

A
  1. glucuronidation: sugar moiety transferred to phase 1 metabolite groups
  2. sulfation: sulfotransferase
  3. acetylation: acetyltransferase
  4. glutathione conjugation: glutathione S transferase
  5. fatty acid conjugation
  6. condensation reactions
  7. amino acid conjugation
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20
Q

Aspirin Metabolism

A
  • aspirin hydrolysis to salicylic acid (liver activation)

- form ether glucuronide or sulfate, ester glucuronide, salicyloyl glycine

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21
Q

Glucuronidation

A
  • addition of sugar moiety
  • conjugation to a-D-glucuronic acid
  • most important path for drug metabolism
  • products excreted in bile
  • uses UDP-glucuronosyltransferase enzyme
  • conjugates -OH, -COOH, -NH2, -SH, C-H
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22
Q

a-D-glucoronic acid

A
  • cofactors binds to gluco-transferase to help transfer the sugar
    1. phosphorylase adds P to a-D-glucose 1-phosphate
    2. a-D-glucose 1-UDP formed
    3. 2 NADH removed via UDPG dehydrogenase
    4. a-D-glucose 1-UDP-glucoronic acid
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23
Q

N glucuronidation

A
  • occurs with amines (aromatics)

- occurs with amides and sulfonamides

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24
Q

O glucuronidation

A
  • occurs by ester linkages with carboxylic acids

- occurs by ether linkages with phenols and alcohols

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25
Q

Sulfation

A
  • major pathway for phenols, alcohols, amines, and thiols
  • sulfation can make reactive byproducts
  • occurs at lower substrate concentrations
  • PAPS (phosphoadenosine phosphosulfate) is the most common coenzyme in sulfotransferase reactions
  • conjugates -OH, -NH2
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26
Q

Acetylation

A
  • aromatic amines and sulfonamides
  • requires N-acetyltransferase and cofactor acetyl-CoA
  • acetyl-sulfonamides are less soluble than parent compound and cause renal toxicity
  • conjugates -OH, -NH2
27
Q

Fatty Acid Conjugation

A
  • stearic and palmitic acids are conjugated to drug via esterification
  • addition of a large hydrophobic molecule
  • secreted in feces
28
Q

Amino Acid Conjugation

A
  • active CoA amino acid conjugates reacting with drugs by N-acetylation
  • glycine, glutamine, arginine
29
Q

Glutathione Conjugation

A
  • tripeptide Gly-Cys-Glu conjugated by glutathione S transferase
  • conjugated compounds subsequently attacked by g-glutamyltranspeptidase and a peptidase
  • products can be further acetylated
30
Q

Drug Modifications and Metabolism

A
  • can make drugs more or less resistant to metabolism by removing susceptible groups or adding them
  • don’t want a drug breaking down too quickly or become toxic and long lasting
  • ie. methyl easily metabolised so can be exchanged for Cl (or vice versa)
31
Q

Efflux Transporters

A
  • cause multidrug resistance in cancer treatment

- transporters detoxify cells from toxic compounds (P-glycoprotein)

32
Q

Factors affecting metabolism

A
  • rate and pathway of drug metabolism are affected by species, sex, age, hormones, etc
  • drug metabolism is stereospecific where enantiomers act as two different xenobiotics with different metabolites and pharmacokinetics
  • inactive enantiomer can produce toxic metabolites or be dangerous
33
Q

Drug Blood Availability

A
  • drugs can bind to plasma proteins (causes lack of bioavailability)
  • only the unbound compound is available for distribution into tissues
  • acidic drugs tend to bind albumin and basic drugs bind alpha 1 acid glycoprotein
  • can modify drugs to change their plasma binding and bioavailability
  • % plasma binding gives information about the amount actually having an activity
34
Q

Prodrugs

A
  • compounds that are inactive but are converted in the body to an active drug by metabolic enzyme (activated after phase 1 metabolism)
35
Q

Benefits of prodrugs

A
  1. improve membrane permeability
    - esters: if carboxylic acid is important for drug binding but prevents drug from crossing membrane it can be hidden as an ester
    - in the blood the ester is hydrolysed to active form
    - N-methylation: amines methylated to increase hydrophobicity
  2. membrane transport: mimic substrate to cross membrane
  3. extend life
    - 6-mercaptopurine is an immune suppressant eliminated quickly. prodrug slowly converted allows longer activity
  4. less toxicity
    - salicylic acid contains phenolic -OH causing gastric bleeding. aspirin has an ester to mask this toxic group until it is hydrolysed
36
Q

Prodrug Definition

A
  • pharmacologically inactive compound converted to active drug by metabolic biotransformation
  • simple chemical derivatives requiring only one to two chemical or enzymatic transformation steps to yield the active parent drug
  • prodrug to drug conversion can occur before/during/after absorption or in a specific site
37
Q

Utility of prodrugs

A
  • improved ADMET properties
    1. absorption: improve
    2. distribution: modify to cross blood brain barrier
    3. metabolism and excretion
    4. toxicity: alleviate toxic burden
  • potentially easier to formulate or administer
38
Q

Prodrug activating enzymes

A
  • mostly esterases

- found in many tissues in different cellular locations

39
Q

Biopharmaceutical Classification System

A
  • characterisation of drugs based on solubility and permeability measures
    1. high solubility and high permeability : water soluble
    2. low solubility and high permeability : prodrug optimise
    3. high solubility and low permeability : prodrug optimise
    4. low solubility and low permeability : membrane target
40
Q

Types of Prodrugs

A
  1. bio-precursors

2. carrier linked prodrugs: bipartite, tripartite, mutual prodrugs

41
Q

Ideal Drug Carrier

A
  1. protect drug until site of action
  2. localise drug at the site of action
  3. release drug chemically or enzymatically
  4. minimise host toxicity
  5. biodegradable, biochemically inert, nonimmunogenic
  6. easily prepared and inexpensive
  7. chemically and biochemically stable
42
Q

Carrier linked prodrugs

A
  • contains active drug linked to carrier group (generally esters or amides) that can be removed enzymatically (hydrolytic cleavage)
  • esters and amides are major group of carrier linked prodrugs
  • drug molecules contains alcohol/carboxylic acids are esterified
  • bond to carrier group must be labile to allow active drug to be released
  • carrier group non toxic and inactive
43
Q

Esterases

A
  • hydrolase enzymes
  • liberate drug’s active form
  • esters are useful in modifying lipophilicity of drugs
  • aliphatic esters generally enhance lipid solubility whereas phosphate esters improve aqueous solubility
44
Q

Prodrug Funcational Groups

A
  • consider which functional groups are amenable to chemical prodrug derivatisation
  • these are typically carboxylic, hydroxyl, amine, phosphate, and carbonyl groups
  • prodrugs produced via modification of these groups include esters, carbonates, carbamates, amides, phosphates, and oximes
45
Q

Functional Group Modifications

A
  1. hydroxyl, carboxyl, and amine
  2. esters
  3. sulfenamides
  4. carbamates
  5. phosphate groups
  6. amidine or guanine groups
    - all have esterases breaking an ester bond to release drug
    * * review notes **
46
Q

Alcohols and carboxylic acids

A
  • most common prodrug form are esters
  • esterases are ubiquitous
  • esters alter lipophilicity : any degree of hydrophobicity can be made to facilitate membrane diffusion
  • challenging the predict their pharmacokinetics
  • significant differences in specific esterase activities in preclinical species
47
Q

General Mechanism of Esterases

A
  • contain catalytic triad: His, Ser, Asp
  • ester come into binding site
  • His deprotonates Ser-OH
  • Ser attacks the ester bond
  • covalent tetrahedral intermediate
  • release of alcohol
  • water enters and is deprotonated for attack on Ser
  • release of second alcohol and the bioactive product
    • see NOTES **
48
Q

Water Solubility

A
  • alcohol containing drugs acylated with aliphatic acids to decrease water solubility or with carboxylic acids to increase water solubility
  • phosphate or sulfate esters also increase water solubility
  • aromatic or aliphatic functional groups increase hydrophobicity
  • phosphate functional groups enhance solubility
    • see NOTES **
49
Q

Prodrug Aqueous solubility

A
  • prodrugs can overcome solubility limitations of poorly soluble drugs when phase 1 metabolism is low to moderate
50
Q

Improved lipophilicity

A
  • prodrugs frequently mask polar and ionisable groups to improve oral drug delivery
  • promotes membrane permeability and oral absorption
51
Q

Examples of Prodrugs

A
  • phosphate often used to increase solubility
    eg. Fosamprenavir (antiviral) containing a phosphate ester of amprenavir. Bioconversion by alkaline phosphatases to increase solubility by 10 times
52
Q

Improved parenteral administration

A
  • increase water solubility by an ionizable/polar promoiety
    to the parent drug
  • increase in solubility imparted by phosphate group is several orders of magnitude
53
Q

Improved topical administration

A
  • opthalmic and dermal
  • unfavorable physiocochemical properties of many drug molecules lead to poor permeation across the skin
  • balance of the two solubilities improves drug permeation
54
Q

Carrier mediated absorption

A
  • prodrugs targeted towards specific membrane transporters are designed to have structural features that would allow them to be taken up by one of the endogenous transporters present at intestinal epithelium
  • target specific transporters for polar or charged drugs
  • peptide transporters are attractive targets
55
Q

Site selective drug delivery

A
  • site selectivity may be achieved in 4 ways: passive enrichment in the organ/transporter mediated delivery/selective metabolic activation through enzymes/antigen targeting
  • usually targeting of the CNS, tumours, and liver targeting
56
Q

Proloinged drug action

A
  • highly lipophilic prodrugs are slowly released from injection site and result in a prolonged duration of action
  • rapid conversion on release
    eg. conversion of nonsteroidal anti-inflammatory drug to glycine conjugate increases potency and extends concentration from 1 to 9 hours due to slow hydrolysis of the amide linkage
57
Q

Bipartite prodrug

A
  • one carrier attached directly to the drug
  • modified lipophilicity due to the carrier
  • hydrolytic cleavage releases the drug
  • carrier is degraded and released
    eg. Latanoprost is used to treat glaucoma. The morelipophilic isopropyl ester prodrug is hydrolysed by corneal esterases to give the biologically active soluble acid
58
Q

Tripartite prodrug

A
  • carrier connect to drug through a linker (enzyme cleaved)
  • modified lipophilicity due to carrier
  • hydrolytic cleavage releases the drug
  • linker spontaneously cleaved
    e. g Ampicillin has poor oral absorption but pivampicillin is a ester tripartite prodrug of the drug. Prodrug uses a -CH2 linker to link ampicillin and pivalic acid carrier. Ester has more lipophilicity and therefore greater bioavailability
    • SEE NOTES **
59
Q

Tripartite Mechanism of Activation

A
  1. ester hydrolysis by esterases to release carrier
  2. spontaneous removal of the linker and release of formaldehyde
  3. release of active drug
60
Q

Mutual Prodrug

A
  • two synergistic drugs attached to each other
  • one drug is the carrier for the other
  • both are active drugs
    eg. Sultamicillin is mutual tripartite prodrug of ampicillin and sulbactam
  • gives improved pharmacokinetic properties and both drugs in combination work better on bacteria to prevent resistance
61
Q

Bioprecursors

A
  • metabolised by molecular modification into a new compound which is the active principle or which can be metabolised further to the active drug
  • unlike carrier linked prodrugs that are active drugs linked to a carrier and released by hydrolysis: bioprecursors cannot be converted to the active drug by simply cleavage of a group of the prodrug
  • activated in the body by oxidation or reduction (phase 1 metabolism)
    eg. sulfasalazine activated by reduction of its azo bond by anaerobic bacteria in the lower bowel to mesalazine and sulfapyridine: anti-inflammatory and antibacterial agents are the product
  • increases the amount of bioavailable compound
62
Q

Macromolecular drug carrier systems

A
  • absorption and distribution of the drug depend on physicochemical properties of the carrier
  • Pros: specific site target, low toxicity
  • Cons: maybe not well absorbed/immunogenic
  • use of glycoproteins, lipoproteins, hormones, ADC, peptides, etc
63
Q

Prodrug Challenges

A
  • complex synthesis
  • controlling site and rate of bioconversion and metabolism
  • interpretation of the preclinical results is complicated by species differences in prodrug bioconversion
  • complex analytical profiling is needed and requires analysis of the prodrug, parent drug, and each metabolite
  • toxicity of not only prodrug and drug but also the released promoieties or byproducts needs to be considered
  • stability must be adequate to allow drug synthesis at scale

Protein Science (11 decks)

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