Pharmacokinetics Part II

Debrisoquine is a antihypertensive drug oxidized by which CYP enzyme?

Which ratio can be used to measure how effectively this enzyme metabolizes Debrisoquine?

Does a high value of this ratio mean better metabolism or worse?

2D6

Parent Drug: oxidized metabolite

• high value (>10) = poor metabolism

• extensive metabolizer= 0.1-10

• low value (<0.1) = ultrarapid metabolism

what is the metabolite of oxidation of Debrisoquine by CYP2D6?

4-OH Debrisoquine or

1-OH debrisoquine

which CYP2D6 alleles allow for normal metabolism?

*1 and *2

which CYP2D6 alleles allow for ultrarapid metabolism ?

would you need to take a higher or lower dose of Debisoquine?

duplication of *2

higher dose bc/ drug is getting metabolized extensively

which CYP2D6 alleles allow for intermediate metabolism (less than normal) ?

would you need to take a higher or lower dose of Debisoquine?

*9, 10, 17, 41

lower dose bc/ its not being elminated effectively

which CYP2D6 alleles allow for poor/no metabolism ?

would you need to take a higher or lower dose of Debisoquine?

*3, 4, 5, 6,

lower dose bc/ its not being elminated from body

to remember: they’re just little kids, they cant eliminate effectively

more than ____ variants in the CYP2D6 gene have been identified

75

does *10 have even more reduced metabolism than *9, 17, 41?

YES but not to the extent of 3, 4, 5, 6 which are POOR

lets say Mark gets diplotype *2 from his dad and *6 from his mom

how well would he metabolize Debisoquine?

would you need to increase or decrease his dose?

*2 = 1

*6 = 0

activity level = 1+ 0 = 1

mark is considered an intermediate metabolizer

he should take lower doses of depisoquine since his body cannot properly eliminate the drug from his system

if a person has poor metabolizer through CYP2D6 would they need a higher or lower dose of codeine?

higher dose bc/ codeine is not being converted to more active morphine through CYP2D6

would you see higher or lower concentrations of morphine in a patient who is a CYP2D6 UM?

what would you expect to see in these patients?

increased concentrations of morphine bc/ CYP2D6 is ultrarapid leading to higher conversion of codeine to morphine

may experience side effects such as CNS and respiratory depression bc/ of enhanced analgesic

Mark’s mom has a diplotype of *9/*3

Mark’s dad has a diplotype of *4/*5

Mark inhereted *3/*4

how does each person in the family metabolize through CYP2D6?

mom = 0.5 + 0 = 0.5 (intermediate metabolizer)

dad= 0 + 0 = 0 (POOR metabolizer)

mark = 0+0 = 0 (POOR metabolizer)

what is the indication for Tamoxifen and which enzyme is it metabolized by?

tamoxifen is a SERM

selective estrogen receptor modulator for ER+ breast cancer

metabolized by CYP2D6

tamoxifen is a prodrug

what is its activated metabolized form?

which enzymes allow it to react its activated form?

active metabolite = N-desmethylTAM and endoxifen (100x stronger)

tamoxifen —> N-desmetylTAM (using CYP3A4/5) —> endoxifen (CYP2D6)

OR

tamoxifen —> 4 hydroxytam (CYP2D6) —> endoxifen (CYP3A4/5)

what are the two ways tamoxifen can get metabolized into its active form?

tamoxifen —> 4- hydroxyTAM (CYP2D6) —> endoxifen (CYP3A4/5)

tamoxifen —> N-desmethylTAM (CYP3A4/5) —> endoxifen (CYP2D6)

explain why you would see higher endoxifen concentrations in patients with diplotype *1/*1 compared to *1/*varient and varient/varient

*1/*1 is the extensive metabolizer (normal) of tamoxifen giving greatest endoxifen levels in the plasma

Are ER+ breast cancer relapse times shorter and outcomes worse for those who are poor CYP2D6 metabolizers or ultrarapid CYP2D6 metabolizers?

POOR CYP2D6

tamoxifen must be metabolized by CYP2D6 to be effective

what is recommended before initiating tamoxifen treatment in ER+ breast cancer patients ?

genetic testing to see if they have the diplotype alleles that makes them poor CYP2D6 metabolizers

if they do have poor CYP2D6 metabolism then you should consider prescribing them aromatase inhibitor such as letrozole instead of tamoxifen

would you recommend an aromatase inhibitor instead of tamoxifen to a CYP2D6 ultrarapid metabolizing patient or a CYP2D6 poor metabolizing patient?

CYP2D6 poor metabolizing patient bc/ they wont be able to convert tamoxifen to its active form endoxifen

which CYP2D6 metabolizers would you start with the standard dose of tamoxifen?

ultrarapid metabolizers and

normal(extensive) metabolizers

the following recommendation would be given to which CYP2D6 metabolizer:

consider aromatase inhibitor or use higher tamoxifen dose

intermediate CYP2D6 metabolizer

they can still metabolize to active form so you can try increasing the dose still

the following recommendation would be given to which CYP2D6 metabolizer:

consider aromatase inhibitor (letrozole, anastrozole)

CYP2D6 poor metabolizers

upping the dose of tamoxifen would not increase your chances of having higher endoxifen bc/ your body is not metabolizing tamoxifen unliek intermediate

should you prescribe moderate/strong CYP2D6 inhibitors if prescribing tamoxifen?

NO bc/ you need CYP2D6 for tamoxifen to be activated

Which diplotypes would lead to poor metabolism by CYP2C19?

would you increase or decrease the dose of drugs metabolized by CYP2C9?

which population is most often seen with this diplotype?

*2/*2 , *2/*3, *3/*3

use alternative therapy overall

south asians

which diplotypes would lead to ultrarapid metabolism by CYP2C19?

would you increase or decrease the dose of drugs metabolized by CYP2C9?

*17/*17 and *1/*17

should be able to administer standard dose

which diplotypes would you see in an individual who has normal metabolism (extensive) through CYP2C19?

*1/*1

which diplotypes would you see in an individual who has intermediate metabolism (extensive) through CYP2C19?

would you increase or decrease the dose of drugs metabolized by CYP2C9?

*1/*2 or *1/*3

give alternative therapy

omeprazole and lansoprazole are ___________ _____ _________ that __________________ and _____________

used to treat _____ ______ __________

inactivated by ________

proton pump inhibitors

reduce stomach acid secretion and increase pH

ussed to treat peptic ulcer disease

inactivated by CYP2C19

are omeprazole and lansoprazole activated or deactivated by CYP2C19 ?

DEACTIVATED

what effect does poor metabolism by CYP2C19 have on the efficacy of proton pump inhibitors such as omeprazole and lansoprazole?

poor metabolism of CYP2C19 is favored as it allows the action to last longer since drugs are not being deactivated through metabolism

do patients with CYP2C19 UM or PM have higher PPI drug levels, AUC, better pH changes, and enhanced ulcer cure rates?

CYP2C19 PM

antiplatelet drug used as secondary prevention of atherothrombotic events following an MI, stroke, and peripheral artery disease

clopidogrel

is clopidogrel activated by or inactivated by CYP2C19 ?

activated

clopidogrel is a prodrug

patients with a loss of function CYP2C19 SNP are at an increased risk of ________ _______ events

why is this the case?

MI (myocardial infarction)

CYP2C19 is used to activate clopidogrel. those with poorer metabolism( 2/3 2/2 3/3) are at increased risk since activated clopidogrel is meant to prevent MI events through its antiplatelet activity

nonnucleoside RT inhibitor to treat HIV

Efavirenz

high levels of Efavirenz (due to poor metabolism) may increase risk of ___________ (_______, ________)

low levels of Efavirenz (due to high metabolism) may lead to ______ _________

high concentration (poor metabolism) = neurological disease (hallucinations, sleep disorders)

low concentration (high metabolism) = virologic failure

which enzyme deactivates Efavirenz (HIV treatment)

what is the name of the deactivated drug?

CYP2B6 metabolizes efavirenz into inactive 8-hydroxyefavirenz

which enzyme is used to inactivate the glucuronide conjugate of Efavirenz ?

UGT N-glucuronidation

There is an additional category for CYP2B6 metabolism which is________ _______

Which diplotypes fall under this new category?

rapid metabolizer (not as rapid as ultrarapid metabolizer)

*1/*4 or *1/*22

which diplotypes lead to CYP2B6 ultrarapid (UM) metabolism?

should you increase or decrease the normal 600mg//day dose of Efavirenz?

*4/*4 or *22/*22

don’t need to adjust dose of Efavirenz

which diplotypes lead to CYP2B6 nromal/ extensive metabolism (EM/NM) ?

should you increase or decrease the normal 600mg//day dose of Efavirenz?

*1/*1

don’t need to adjust dose of Efavirenz

which diplotypes lead to CYP2B6 intermediate metabolism (IM)?

should you increase or decrease the normal 600mg//day dose of Efavirenz?

*1/*6 *1/*18

*4/*6 *4/*18

*22/*6 *22/*18

Decreased the dose of Efavirenz as intermediate metabolism will allow efavirenz to accumulate in the blood leading to neurological defects such as hallucinations and sleep disorders

which diplotypes lead to CYP2B6 Poor Metabolsim (PM)?

should you increase or decrease the normal 600mg//day dose of Efavirenz?

*6/*18 *6/*6 *18/*18

lower dose to avoid toxic levels of efavirenz in the blood leading to neurological disorders such as hallucinations and sleep disorders

Which enzyme inactivates NSAIDs?

CYP2C9

what is the MOA of the Non Steroidal Ani-Inflammatory Drugs (NSAIDs) ?

inhibits cyclooxygenases (COX) which normally converts Arachidonic Acid into Prostaglandin

What can toxicities in NSAIDs (due to poor metabolism by CYP2C9) lead to?

GI, renal, cardiovascular toxicity

CYP2C9 SNPs impact PK of

slightly different guidelines for

________, ________, and __________

• intermediate/poor metabolizers are at greater risk for toxicity

1. ibuprofen

2. flurbipofen

3. celecoxib

4. lornoxicam

different for meloxicam, piroxicam, tenoxicam

What are the reference diplotypes for CYP2C9 ?

What is the activity score?

*1/*1

1+1 = 2

What are the diplotypes for the intermediate metabolizer (IM)?

what are the activity scores for each of the diplotypes?

what should the doses be?

*1/*2 (1+0.5) = 1.5 (normal dose)

*2/*2 (0.5+0.5) = 1 (lowest starting dose)

*1/*3 (1+0) = 1 (lowest starting dose)

What are the diplotypes for the poor metabolizers?

what are the activity scores for each of the diplotypes?

what should the doses be?

*2/*3 (0.5+ 0) = 0.5

*3/*3 (0+0) = 0

Give 25-50% of the lowest recommended starting dose OR alternative therapy not metabolized by CYP2C9, including aspirin, ketorolac, naproxen, and sulindac

which medication is widely used as an immunosuppressive medication used to prevent transplant rejection

tacrolimus

tacrolimus binds to ________ ________ ( ______ binding protein) and inhibits _________ which is responsible for dephosphorylating ________ transcription factor

This reduces the transcription of IL-2 and prevents T cell activation

immunophilin FKBP12 (FK506 binding protein)

Inhibits calcineurin, which dephosphorylates NFAT

Tacrolimus has a narrow therapeutic index and large interpatient PK variability

Tacrolimus is metabolized by ________ and ________

What is their method of metabolism?

Polymorphisms in ________ influence phenotypic variation

tacrolimus is metabolized by CYP3A4 and CYP3A5

demethylation and hydroxylation

CYP3A5

what are the three different modes of CYP3A5 metabolism?

• extensive metabolizer (EM)

• intermediate metabolizer (IM)

• poor metabolizer (PM)

What is the diplotype for extensive/normal metabolism of tacrolimus metabolism by CYP3A5?

what dose is recommended for individuals with this diplotype?

*1/*1

increase starting dose (1.5-2x recommended dose)

What is the diplotype for intermediate metabolism (IM) of tacrolimus metabolism by CYP3A5?

what dose is recommended for individuals with this diplotype?

*1/ *3

*1/ *6

*1/ *7

increased starting dose (1.5-2 starting dose)

What is the diplotype for intermediate metabolism (IM) of tacrolimus metabolism by CYP3A5?

what dose is recommended for individuals with this diplotype?

*3/*3 *3/*6 *3/*7

*6/*7 *7/*7 6*/6*

start with standard recommended dose and then TDM

CYP3A5 ___ and ____ have decreased trough concentrations of tacrolimus and compared with those who are CYP3A5 ____, possibly delaying acheivement of target blood concentrations

HOWEVER starting dose should never exceed ______mg/kg/day

Extensive Metabolizers and Intermediate Metabolizers of CYP3A5 require heightened 1.5-2 times recommended starting dose

normal dose needed for Poor Metabolizers of CYP3A5

0.3

fluoropyrimidines are used for treating ______ ________

5-fluorafacil and its prodrug _________

10-40% of patients develop severe and sometimes life-threatening toxicities such as _________, ______, _______, ________, ________, and _________)

solid tumors

capecitabine

neutropenia, nausea, vomiting, diarrhea, stomatitis, mucositis

Fluropyrimidines and DPYD:

Capecitabine —> 5” DFCR (using ____________)

5”- DFCR ——> 5’ DFUR (using ____________)

5’DFUR—→ 5-FU (using ___________)

carboxyl-esterase

cytidine deaminase

thymidine phosphorylase

_________________ ___________ (______) is encoded by _____ gene

1st and rate limiting step in metabolising 5-FU—→ _________

Reduced _____ activity

• increases t1/2 of 5-FU due to reduced clearance

• dose related toxicities

Recommendations

• ______ reduce dose by 25-50%

• _____: use a different drug

dihydropyrimidine dehydrogenase (DPD) encoded by DPYD gene

dihydroflouracil (DHFU)

DPD

IM

PM

The UGT2A locus encodes for ___ UGT1A proteins

There are also ___ pseudogenes in the locus (nonfunctional DNA that resembles functional DNA)

9

4

exon ___ is unique for each of the 9 UGT1A proteins

exons ___-____ are the same for each of the 9 UGT1A proteins

1 is unique

2-5 are the same

DISPOSITION OF BILLIRUBIN:

Outside of the sinusoid, unconjugated bilirubin is bound to ________

Within the space of ________ unconjugated billirubin is freed from _______ and enters the hepatocyte

In the hepatocyte, the unbound unconjugated bilirubin gets conjugated using ________

It then undergoes further _________ by __________

NOW it is able to get into the bile through MRP2!

• albumin

• disse albumin

• GST

• glucoronidated UGT1A

inherited genetic disease that results from (near) complete or complete loss of UGT1A1 due to mutation in the coding sequence

Criglet-Najjar Syndrome

which type of Crigler-Najjar Syndrome is due to highly deficient UGT1A

which type of Crigler-Najjar Syndrome is due to NO UGT1A

Type 2= highly deficient

Type 1= COMPLETEY deficient (MORE SEVERE)

why is the loss of UGT1A so critical as seen in Crigler-Najjar SYndrome?

UGT1A glucoronates bilirubin and allows it to enter the bile

if Billirubin is left unconjugated it is able to reach the blood-brain barrier, where it can lead to neurotoxicity (Kernicterus)

If unconjugated bilirubin due to Crigler-Najjar Syndrome reaches the BBB then there is a potential for kernicerus, which leads to

• __________

• increased/decreased muscle tone

• ______ and _______ disabilities

lethary

increased muscle tone

motor and intellectual

how has Crigler - Najjar Syndrome been treated?

certain wavelengths of blue light (430-490) convert billirubin to water soluble forms to be eliminated

Gilbert’s Syndrome occurs when ___ copy of UGT1A1 gene has a mutation

• The most common polymorphism is ____________

• Is Gilbert’s syndrome more or less severe than Crigler-Najjar Syndrome

• ____% increase in serum bilirubin levels

• often ______ descent

• 1

• less severe than Crigler-Najjar

• 60%

• asian

antiretroviral protease inhibitor against HIV infection that inhibits the UGT1A1 glucuronidation of bilirubin

Atazanavir

a patient’s plasma concentrations is tested and they have increased serum levels of bilirubin, patient tests negative for hepatotoxicity ,what is a possible explanation?

patient is on Atazanavir which decreases their UGT1A1 levels. UGT1A1 usually removed bile from blood and into bile duct but with low levels of this enzyme patient now experiences hyperbilirubinemia

________(CPT-11) is a prodrug used in the chemotherapy of solid tumors

What activates this enzyme, and what is the enzyme activated into?

What does the activated form of this drug do?

Irinotecan

carboxylesterases activate irinotecan into SN-38

inhibit the topoisomerase I of cancerous cells

what role does UGT1A1 have in Irinotecan action?

what happens if there is a UGT1A1 deficiency?

UGT1A1 inactivates the activated form of Irinotecan (SN-38) turning it into SN-38 glucoronide

if UGT1A1 is deficient then there will be toxic levels of SN-38 leading to leukopenia, neutropenia, intestinal cell damage (diarrhea)

explain how a patient on Irinotecan with Gilbert’s syndrome could experience dramatic decreased neutrophil counts

irinotecan is converted into its activated form SN-38 using carboxylesterase

Gilbert’s syndrome decreases UGT1A1 levels causing increased toxic levels of SN-38

SN-38 can be drained into the small intestine from the bile duct and come back into the blood stream from the intestine

increased SN-38 in the blood leads to neutrophil death

what specific UGT1A1 mutation decreases its activity leading to higher levels of neutrophil death?

if there are more or less than 6 ATA repeats of the TATA box in the promotor region of the UGT1A1 gene

__________ variant results from (TA)7TAA rather than (TA)6TAA

this is relevant when taking which medication?

UGT1A1*28

Irinotecan

Yuji, a Japanese patient was diagnosed with tuberculosis

His pharmacist accidently typed that he he needed to take his isoniazid 3 times daily instead of once a day

Yuji however does not experience any isoniazid toxicity, why is that?

Since Yuji is Japanese he is able to rapidly metabolize isoniazid through acetylation by NAT2 enzyme

Yuji needs a higher dose anyways because of how rapifly his body eliminates isoniazid through NAT2 enzyme

rapid acetylators may need higher/lower doses of isoniazid

higher —> acetylation through NAT2 deactivates drug

which populations would need higher doses of Isoniazid to treat their tuberculosis?

why is this the case?

• eskimos

• japanese

• latin americans

they are very rapid acytelators so you need more of the drug since much of it will be acytelated by NAT2

Adverse toxicities in slow acytelators:

• Isoniazid-induced ______ ________

• Procainamide (antiarrhythmic) and Hydralazine (antihypertensive) induced __________

• Dapsone (antimicrobial) induced________ ________

LOWER DOSES OF THESE DRUGS SHOULD BE ADMINISTERED BC/ OF SLOW ACCELERATION, WHICH WILL KEEP TOXIC LEVELS IN THE BODY LONGER

peripheral neuropathy

lupus erythematosus

hemolytic anemia

lupus erythematosus may be seen in individuals will slowed NAT2 acytelation taking which drugs?

procainamide (antiarrhythmic) and hydralazine (antihypertensive)

hemolytic anemia may be seen in individuals will slowed NAT2 acytelation taking which drugs?

dapsone (antimicrobial)

peripheral neuropathy may be seen in individuals will slowed NAT2 acytelation taking which drugs?

how can this be combated to prevent toxicity of the drug?

isoniazid

vitamin B6 (pyroxidine)

NAT2 metabolizes Isoniazid into which two inactive metabolites?

acetylhydrazine and isonicotinic acid

which medications does TPMT (ThioPurine S- Methyl Transferase) metabolize?

1. 6-mercaptopurine

2. 6-thioguanine

3. azathioprine

TPMT is used to metabolize medications

• 6-mercaptoPURINE

• 6-thioGUANINE

• Azathioprine

What are the indications for these medications?

• leukemia (acute lymphoblastic)

• Inflammatory bowel disease

• transplant

We can measure TPMT activity in ____ _____ _____ (surrogate for drug-metabolizing tissues)

• not reliable in people receiving _____ transfusions in the last ___-___ days

red blood cells

30-60

where can TPMT be found?

red blood cells

azothioprine is the prodrug for __________ which is further metabolized by TPMT into ___________

does the metabolism by TPMT activate or inactivate the drug?

6-mercaptopurine (6-MP) —> 6-methyl-mercaptopurine (using TPMT)

INACTIVATE

SEQ inactivation pathways for 6-mercaptopurine

6- mercaptopurine —> 6-methyl-mercaptopurine (using TPMT)

6-mercaptopurine —> 6-thiouric acid (using Xanthine Oxidase)

6-mercaptopurine —> 6-thiosinic acid (usinh HGPRT)— 6-thioguanine nucleotides —> thiouric acid

SEQ activation of azathioprine

azathioprine —> 6-mercaptopurine—> 6-thionosinic acid (USING HGPRT) —> 6-thioguanine nucleotides

6-mercapturicpurine which is inactivated by TMPT has a narrow therapeutic index associated with ______________

myelosuppression

_______ is associated with 6-mercapturicpurine efficacy and toxicity

TPMT

TPMTH (high activity TPMT) is associated with which alleles?

*1 and *24

TPMTH (low activity TPMT) is associated with which alleles?

*2, 3A, 3B, 3C, 4

what is the most common TPMTL (low activity TPMT) variant in Caucasians ?

Why do they have such low levels of TPMTL?

*3 (5% heterozygous frequency 0.3% homozygous null)

increased protein degradation is the cause of low levels of TPMTL

which patients would you give the highest dose of azathiopurine (prodrug of 6MP) to?

• V/V (*2, 3A,B,C,4 / *2,3A,B,C, 4)

• W/W (*1/*1,*24/*24, *1/*24)

• V/W (*2, 3A,B,C,4 / *1 or 24)

give highest dose to W/W bc/ they will rapidly deactivate 6-MP

lowest dose to V/V bc/ they will poorly metabolize 6-MP, leading to myelosuppression

SEARCH STUDY was the Study of Effectiveness of ________ _______ in ___________ and ______________

Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine

SEARCH was a study with 12,064 patients with prior myocardial infarction

half of the patients were on _____mg other half was on ____mg

out of 6,031 patients on ____mg only 90 suffered from myopathy and rhabdomyolysis

half of 81mg half on 20mg

80mg—> myopathy and rhabdomyolysis