Drug metabolism (3)

Question 1

Polymorphism in drug metabolism

Answer 1

• 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

Question 2

Polymorphism- Alleles and the individual

Answer 2

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

Question 3

CYP2C19 alleles- white only

Answer 3

• *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%

Question 4

CYP2C19- African only

Answer 4

• *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%

Question 5

CYP2C19- Chinese

Answer 5

Question 6

Polymorphism key questions

Answer 6

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

Question 7

Key issues in polymorphism research

Answer 7

• 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

Question 8

Features of polymorphism in research

Answer 8

• 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

Question 9

Polymorphism and toxicity

Answer 9

• 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

Question 10

CYP2D6 Polymorphism and anti-psychotic toxicity

Answer 10

• 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

Question 11

Toxicity and efficacy

TMPT and thiopurines

Answer 11

• 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

Question 12

Irinotecan toxicity and efficacy

Answer 12

• 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?
  *

Question 13

Gilbert’s syndrome and Irinotecan toxicity and efficacy

Answer 13

• 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

Question 14

Polymorphism and efficacy

Answer 14

• 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

Question 15

Polymorphisms and efficacy- opiates

Answer 15

• 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

Question 16

Polymorphisms and boosted efficacy- Proton pump inhibitors

Answer 16

• 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)

Question 17

Polymorphism and loss of efficacy

Clopidogrel

Answer 17

• 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

Question 18

Polymorphisms- relevance and testing

Answer 18

• 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

Question 19

Factors affecting metabolism in the elderly

Answer 19

• 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

Question 20

Neonates

Answer 20

• 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>

Question 21

Neonates continued

Answer 21

• 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-

Question 22

Diet effects on metabolism

Answer 22

• 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

Question 23

Gender effects

Answer 23

• 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

Question 24

Smoking

Answer 24

• 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

Question 25

CYP2A6 and smoking

Answer 25

• 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

Question 26

Drinking

Answer 26

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

Question 27

Cirrhosis

Answer 27

• 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

Question 28

Alcoholism and polymorphism

Answer 28

• 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

Question 29

Summary of drug metabolism

Answer 29

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