PDTI Module 13

Enzyme multiplicity:

several different enzymes may be involved in biotransformation of one drug

Product multiplicity:

Drug is metabolized into several different metabolites

Polyfunctionality

drug may undergo several different reaction types

Phase one metabolism in the liver is done by ___ and makes drugs more ____

CYP450s; hydrophillic

Phase two metabolism in the liver is done by ____ and causes ____

Conjugation: UGTs, ST, NAT2, COMT

Further increases compounds solubility

Most metabolism is done by what cyp?

CYP3A

Label the parts of CYP2D6×2A

CYP: Superfamily

2: Family

D6: Subfamily

6: Individual member/isoform

2A: allele/Haplotype

+

P450s from the same ____ share more than 55% sequence homology

subfamily

Intrinsic factors of drug metabolism?

GENETICS, age, sex, disease

Environmental factors of drug metabolism?

DIET, CONCOMINANT (simultaneous use of) DRUGS, chemical exposure

How does high enzyme activity effect amount of drug in the body?

There will be less drug in the body

What enzyme is high in infants and lower in adults?

CYP2619

Drug exposure is related to what 2 factors?

Cmax and AUC

What is the “wild type”/reference allele for CYP2D6?

CYP2D6×1

What are the allele functional statuses?

uncertain function, unknown, no function, decreased function, normal function, increased function

What are the drug metabolizing phenotype standard definitions?

poor metabolizer, intermediate, normal, rapid, and ultrarapid metabolizer

Phenotype=

allele 1 + allele 2

Two increased function alleles=

ultrarapid

Two no function alleles=

poor

Two normal function alleles=

normal

One no /decreased function + normal function =

intermediate

What is the result of an ultrarapid metabolizer on an active drug to the inactive state?

The drug will become inactive faster. The will be low amount of active drug

What is the result of an ultrarapid metabolizer on an inactive drug to the active state?

Most of the drug will be in the active state

Tmax and Cmax happen quickest with ____ metabolizers as opposed to IM and PM

normal metabolizers

When bioavailability is high, _____ is increased

Half life

When bioavailability is low, _____ is increased

Cmax

What is the largest mammaliam CYP family and contributes to 50% of all drug metabolism?

CYP2 gene family

What is the major substrate, inhibitor, and inducer of CYP1A2?

Substrate: Tizanidine

Inhibitor: Fluvoxamine

Inducer: Smoking

What is the CYP enzyme where PM phenotype more common in Asian populations compared to Caucasian?

CYP2A6

What allele is responsible for gene deletion/ no function in CYP2A6?

*4

What is the substrate and inducer of CYP2A6?

Substrate is NICOTINE and inducer is St. Johns Wort.

No inhibitors

How is nicotine broken down by CYP2A6?

Nicotine > nicotine-iminium ion > Cotinine

What CYP2A6 allele point mutation yields inactive protein in Caucasians?

CYP2A6*2

What CYP displays gene duplication?

CYP2A6*1/*1x2

What are the substrates of CYP2B6?

Efavirenz, Methadone, Sertraline

What are the inducers of CYP2B6?

Efavirenz, rifampin, carbamazepine

Poor metabolizers have the least amount of ____ but the most amount _____

clearance; under the curve

What CYP is polymorphic?

CYP2C8

Given the close proximity of CYP2C8 and CYP2C9, some _____exists between these genes

linkage disequilibrium

What are substrates of CYP2C8?

Glitazones (e.g.,
rosiglitazone,
pioglitazone)
Ibuprofen

What are inducers of CYP2C8?

Rifampin

What are the substrates of CYP2C9?

warfarin, Phenytoin, NSAIDs (e.g.,
ibuprofen

What are inhibitors of CYP2C9?

Amiodarone
Fluconazole
Miconazole

What are inducers of CYP2C9?

Rifampin
St. John’s wort

What are the phenotypes for CYP2C9?

poor, intermediate, and normal?

What are CYP2C9 phenotypes based on?

Activity Score. Poor is 0-0.5

Intermediate is 1-1.5

Normal is 2

What CYP2C9 allele is for decreased function?

*2

What CYP2C9 allele is for no function?

*3

What are the substrates for CYP2C19?

Clopidogrel (pro
drug)
PPIs (e.g.,
omeprazole)
Select SSRIs: Sertraline, Escitalopram, Citalopram
Voriconazole

What are inhibitors of CYP2C19?

Fluvoxamine
Fluoxetine

What are inducers of CYP2C19?

Rifampin
St. John’s wort

What are no function alleles for CYP2C19?

*2, *3

What is the increased function allele for CYP2C19?

*17

What does the AUC of PM look like for Clopidigrel?

It has lower AUC because it is a prodrug???

How do proton pump inhibitors like Omeprazole affect H.pylori?

Poor metabolizers have higher cure rate. Experts suggest to increase dose in NM

What are the substrates for CYP2D6?

Codeine (pro drug)
Tramadol (pro drug)
Paroxetine
Fluvoxamine
Desipramine

What are inhibitors of CYP2D6?

Bupropion
Duloxetine
Quinidine
Fluoxetine

What are inducers of CYP2D6?

None. Not inducible

What are the phenotypes for CYP2D6?

PM, IN, NM, UM

Allele function is measured by what in CYP2D6?

activity score

_____ results in increased function for CYP2D6?

Duplication

What are the substrates for CYP3A4/5?

Tacrolimus
Quetiapine

What are inhibitors of CYP3A4/5?

Ketoconazole
Verapamil
Grapefruit
juice

What are inducers of CYP3A4/5?

Rifampin
Carbamazepine
Phenobarbital
Phenytoin
St. John’s wort

What is a clinically relevant variant for CYP3A4?

*22

What is a functional variant conferring expresser phenotype (NM or IM) for CYP3A5?

*1

What CYP3A5 variant causes splicing defects and truncated protein?

*3

CYP3A5 expresses most commonly in ____

African Americans (2/3)

What are non expresser star alleles for CYP3A5?

*3/*3. Majority of population

What is a phase 1 enzyme that is the rate limiting step for fluoropyrimidines metabolism?

dihydropyrimidine dehydrogenase (DPD), encoded for by DPYD

DPYD is rare and highly ____

polymorphic

Variation leading to _____DPD activity increases exposure to drug and increases risk of life-threatening fluorouracil toxicity

decreased

Why are DPYD variants important?

Variants are rare with low population frequency but have severe clinical consequences

What are substrates of DPYD?

Fluoropyrimidines
(e.g., 5-FU and
capecitabine)

What are the substrates for UGT1A1?

Atazanavir, bilirubin, irinotecan

What is an inducer of UGT1A1?

Rifampin

What are decreased function star alleles for UGT1A1

6 and 28

What ethnic group is frequently a poor metabolizer of UGT1A1?

African americans

SN-38 is transformed into SN-38 glucuronide by what enzyme?

UGT1A1

NAT poor metabolizers

slow acetylators

NAT intermediate/normal metabolizers

fast acetylators

NAT2 substrates

Isoniazid,
hydralazine,
amifampridine

______ acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure

Slow

What does TPMT do?

Thiopurine Methyl Transferase. Catalyzes the s-methylation of thiopurine drugs

What are the substrates for TPMT

Thiopurines (e.g., Azathioprine, 6-mercaptopurine)

What are phenotypes for TPMT?

PM, IM, NM

What does NUDT15 do?

NUDT15 converts a cytotoxic metabolite to a less toxic one

What are phenotypes for NUDT15?

PM, IM, NM

What are substrates for NUDT15?

Thiopurines (e.g., Azathioprine, 6-mercaptopurine)

What are substrates for COMT?

Catecholamine
neurotransmitters

How are Vmax and Km affected in competative inhibition?

Substrate Vmax unchanged, Km increase

How are Vmax and Km affected for non-competitive inhibition?

Vmax and Km both change (Km might not though)

What is AUC ratio and what classifies strong, moderate, and weak?

AUCinhibitor/AUCno inhibitor

Strong: AUC> 5

Moderate: equal to 2< AUC <5

Weak is 1.25-2

Describe the onset of enzyme inhibition

Fast onset and offset. Direct chemical effect

Describe the onset of enzyme induction

Slow onset and offset. Signals protein synthesis

What is the effect of St Johns wort at acute levels?

Inhibits P-gp/CYP3A4

What does grapefruit juice inhibit?

CYP3A4 and OATP

______ is a great resource that has information on the gene, pathways, and dosing recommendations all in one place

PharmGKB