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PH3505- Medicinal chemistry > Drug metabolism (3) > Flashcards

Drug metabolism (3) Flashcards

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1
Q

Polymorphism in drug metabolism

A
  • Genetic variation in a biotransformation isoform which is prevalent in more than 1% of the population
  • Polymorphic form is usually poorly or non-functional
  • Occasionally much more efficient than wild type
  • Alleles and the individual
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2
Q

Polymorphism- Alleles and the individual

A
  • CYP2C19 *1 = Wild type= most common
  • CYP2C19 *2= Almost zero function
  • CYP2C19 *3= Zero
  • CYP2C19 *17= Ultra fast
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3
Q

CYP2C19 alleles- white only

A
  • *1 + *1= Homozygous= EM (extensive metabolism) = 73% (wild/wild type)
  • *1 + *3= Heterozygous = IM (Intermediate) = 25%
  • *1 + *2= Heterozygous= IM = 25%
  • *2+*2= Homozygous =PM (Poor) = 2%
  • *3+*3= Homozygous =PM = 2%
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4
Q

CYP2C19- African only

A
  • *1+*1= Homozygous = EM = 66%
  • *1+*3= Heterozygous =IM = 29%
  • *1+*2= Hetero =IM = 29%
  • *2+*2= Homo. =PM = 4%
  • *3+*3= Homo. =PM = 4%
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5
Q

CYP2C19- Chinese

A
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6
Q

Polymorphism key questions

A
  • Real world relavence to drug use in the clinic
  • Should genetic testing for polymorphisms be routine
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7
Q

Key issues in polymorphism research

A
  • A large number of molecular biological studies determining alleles
  • A small number of actual clinical studies to determine relevance
  • Established ‘Wisdom’ CYP2D6 and nortriptyline based on <200 patients and nine studies
  • Tiny study numbers to predict the effects in millions ‘Vioxx’
  • CYP2C19*17 = Ultra fast metabolizers alleles
  • Found in 18% of Swedes and Ethiopians
  • Only 4% of Chinese
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8
Q

Features of polymorphism in research

A
  • Many studies only record drug/metabolite levels
    • Nothing about toxicity and efficacy
  • Multiple pathways/Metabolites active difficulties in measuring toxicity / efficacy
  • Consideration of some polymorphisms with respect to toxicity/ Efficacy
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9
Q

Polymorphism and toxicity

A
  • The main toxic issue in drug design Therapeutic
  • E.g. Tordades des pointes (TdP)
  • Long QT interval (>0.45 sec) heart cannot repolarise fast enough
  • A lot of drugs can cause this but only in high concentration- such as being a PM or having an enzyme inhibitor
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10
Q

CYP2D6 Polymorphism and anti-psychotic toxicity

A
  • A quarter of white people have CYP2D6 *4
  • 7-10% of White - *4+*4 - no functional CYP2D6
  • Anti-psychotics partly cleared by CYP2D6 and Schizophrenia on old drugs twice as likely to die of TdP
  • In UK ~18,000 people who are schizophrenic and *4+*4
  • BUT 2009 study risk is the same for new (NON-CYP2D6) agents
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11
Q

Toxicity and efficacy

TMPT and thiopurines

A
  • Azathioprine/Mercaptopurine act through 6-TG metabolites
  • 6-TG metabolites- efficacy and toxicity cleared by TPMT
  • <10% impaired TPMT = toxicity
  • <2% Ultra-rapid clearance = loss of efficacy
  • Is genotype testing enough?
  • NO: Effect of salicylates/GST/TPMT induction
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12
Q

Irinotecan toxicity and efficacy

A
  • Topoisomerase I inhibitor- used in bowel and rectal cancers
  • SN-38 active metabolite cleared by UGT1A1
  • >> SN-38 more toxic (lung/neutropenia/gut) and effective
  • Role of UGT polymorphism?
    *
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13
Q

Gilbert’s syndrome and Irinotecan toxicity and efficacy

A
  • UGT1A1 *28/*28 homozygous: 70% reduction in function- metabolises bilirubin
  • ~7% of human population are *28+*28
  • Some Gilbert’s individuals little SN-38 toxicity, others high toxicity
  • Role of UGT1A7- 5 fold higher SN-38 clearance than UGUT1A1
  • UGT1A7 subject to W208R and 57/TG polymorphisms
  • Need to test for three polymorphisms in 2 isoforms of UGT
  • Bilirubin is a strong anti-oxidants which protects cells
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14
Q

Polymorphism and efficacy

A
  • Many opiates cleared by CYP2D6 to active metabolites (Codeine, Oxycodone, Hydrocodone, Tramadol)
  • Are these drugs useless in CYP2D6*4+*4?
  • Tramadol-demethylated to M1, 200-fold more potent than parent on opiate receptors
  • SLANAR et al physiolRes 56:129-136, 2007
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15
Q

Polymorphisms and efficacy- opiates

A
  • Even in *4/*4 M1 appears and it slowly cleared
  • It does have a therapeutic effect
  • M1 cleared by UGTs
  • Parent has activity also
  • Net effect tramadol has some analgesic effect in virtually everyone
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16
Q

Polymorphisms and boosted efficacy- Proton pump inhibitors

A
  • Ulcer treatment- 7 days antibiotic plus PPI
  • Cure rates 100% in CYP2C19*2+*2
  • Only 60% in wild-type and heterozygotes
  • PPI’s up to 14 fold higher in PMs than wild-types and heterozygotes
  • PPI dosage must be increased: especially in *17+*17
  • I.e. better in worse metabolised, longer residence time (NB- only good for relatively non-toxic drugs)
17
Q

Polymorphism and loss of efficacy

Clopidogrel

A
  • Active thiol blocks ADP receptors on platelets
  • Homozygote non-functional CYP2C19= treatment failure
  • Non-functional CYP2C19 in 14% chinese/koreans, 1-4% other races
  • Answer prasugrel-cleared by esterases and several CYPs- people proof means that if one enzyme if faulty another can still metabolise it
18
Q

Polymorphisms- relevance and testing

A
  • Narrow TI drugs-potentially fatal adverse reactions
  • When genotype is strong predictor for efficacy
  • Phenotyping provides more information than genotyping alone (therapeutic monitoring)
  • Cost effectiveness: at $200 per test- worthwhile for long term therapy
  • Problem drug may be superseded in some areas, but not others
19
Q

Factors affecting metabolism in the elderly

A
  • Liver blood flow: 40% lower in the elderly
  • Renal function impaired (diabetes, obese, HTN)
  • Polypharmacy + depression
  • Main drugs affected: high intrinsic clearance drugs (propranolol, metoprolol, pethidine)
  • Low intrinsic clearance drugs (Phenytoin, diazepam, NSAIDs)
  • As extraction is low, changes cause large changes in plasma levels
  • SSRIs added to complex regimens to treat depression
  • In general, drug levels in the elderly can be more than double that of a normal adult
20
Q

Neonates

A
  • Poor renal clearance (vancomycinAmpicillin)/ Immature CYPs
  • Drug clearance can be 10 times slower than adults
  • Premature neonates even slower (<half>
    </half><li>By 6 months old, many CYP differences virtually gone</li><li>Conjugation 'Phase II' systems mature very slowly hence yellow babies</li><li>Glucuronidation not mature by 1-2 years</li><li>Several drugs have much longer half-lives (&gt;4 fold) in young children </li><li>E.g. NSAID's, morphine derivatives, lorazepam, oxazepam, AZT- they lack UGT's</li>

</half>

21
Q

Neonates continued

A
  • Paracetamol cleared half as quickly in neonates compared with older children
  • Paracetamol metabolism different: neonates clear to a sulphate
  • Neonates resistant to paracetamol toxicity: lack of CYP2E1-
22
Q

Diet effects on metabolism

A
  • Barbecued meat: CYP1A1/2- Increased clearance of clozapine, caffeine, theophylline, haloperidol
  • Cruciferous vegetables, broccoli, cabbage, sprouts
  • Complex mix of inducers and inhibitors in vegetables: net effects are individual
23
Q

Gender effects

A
  • Females generally clear drugs more quickly than males
  • Particularly seen with CYPs 3A4/2C9: steroids, macrolides, statins
  • CYP3A4 and 2C9 susceptible to sex-hormone cyclic changes
  • Phenytoin effect in female epileptic drug falls out of the therapeutic window
  • Effects of the menopauseHormone replacement
24
Q

Smoking

A
  • Increase in caffeine metabolism, theophylline
  • The mysterious case of those people that can smoke OPs
  • Nicotine cleared by CYP2A6 low expression of this CYP particularly in some Asian population
  • CYP1A1 and 1A2 are induced by smoking- if on clozapine, and stop smoking lead to toxicity as induction effect will wear off
25
Q

CYP2A6 and smoking

A
  • Clears nicotine
  • 20% of japanese are *4C (absent)
  • Low 2A6, low tobacco comsumption, easy to stop
  • Low cancer rates
  • Caucasians *2 absent isoform-rare (>3%)- more likely to smoke more
26
Q

Drinking

A
  • Normal drinkers, little effects on drug clearance
  • Moderate-Heavy drinkers: warfarin clearance increased, TCA clearance reduced
  • Early cirrhosis develops relatively little effects
27
Q

Cirrhosis

A
  • Liver extensively damaged, portal HTN large areas replaced by fibrous tissue
  • High CYP2E1 induction: danger of paracetamol toxicity but drug clearance compromised
  • High extraction drugs
    • Pethidine, metoprolol, propranolol, verapamil
    • 2-7 fold increase in F for opiates and b-blockers
  • Low extraction drugs
    • Phenytoin, paracetamol, diazepam, naproxen, metronidazole
    • 2-5 fold increase in F. for theophylline and warfarin
28
Q

Alcoholism and polymorphism

A
  • 90% of ethanol clearance is through ADH/ALDH
  • High tolerance to ethanol >>> likelihood of addition
  • ADH1B*1 most efficient and main ethanol- clearning variant
  • Found in Caucasians/US indians
  • *2 and ADH1C*2 very inefficient (chinese/japanese)
  • Best combination for alcoholism is ADHB*1 and ALDH2*1+*1
  • ALDH2*2 useless (Eastern races)
  • 20% of eastern alcoholics have deficient ALDH
29
Q

Summary of drug metabolism

A
  • Women tend to clear drugs faster than men due to increased CYP3A4
  • Disease- liver, kindey, diabetes (obesity)
  • Alcohol- cirrhosis= liver enzyme

PH3505- Medicinal chemistry (29 decks)

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