Transplantation

Question 1

Life saving transplantation (no alternative)

Answer 1

Liver
Heart
Heart Lung
Multi visceral

Question 2

Most common organ transplant

Answer 2

Kidney

Question 3

About 50% of all therapeutic agents are metabolized by

Answer 3

CYP3A4 and CYP 3A5

Question 4

About 20% metabolized by

Answer 4

CYP2D6

Question 5

The Transplant patients require for the most complex drug therapy:

Answer 5

Pretransplant long-standing organ failure
Surgical intervention and its complication
Donor-recipient relationship (diff HLAs)
Drug therapy: delicate balance required- organ rejection (if too little); infection/toxicity/cancer (if too much)

Question 6

Calcineurin Inhbitor (CNI)

Answer 6

Cyclosporine (CSA, Neoral)

Tacrolimus (FK, Prograf)

Question 7

Corticosteroids

Answer 7

Prednisone, Methylprednisolone

Question 8

Antimetabolites

Answer 8

Azathioprine (AZA, immuran)
Mycophenolic Acid Mofetil (MMF, Cellcept)
Mycophenolic Acid (Myfortic)

Question 9

mTOR Inhibitors

Answer 9

Sirolimus (Rapamycin, Rapammune)

Everolimus (Zortress)

Question 10

Antibody products

Answer 10

Antithymocyte Globulin (ATG)
Thymoglobulin
Rituximab (Rituxan, CD20 antagonist)

Question 11

What do immunosuppressants block

Answer 11

The pathway for T cell activation

Question 12

Each of these factors will influence the Pharmacokinetics of CNI, Steroids/mTOR Inhibitors

Answer 12

Metabolic enzymes: liver and small intestine- CYP3A4 and CYP3A5
Transport Protein- MDR1: P-Glycoprotein

Question 13

Major Immunosuppressants

Answer 13

Cyclosporine, Tacrolimus, Sirolimus

Question 14

Calcineurin Inhibitors

Answer 14

Backbone of immunosuppression

Cyclosporin & Tacrolimus

Question 15

CNI/TOR inhibitors characteristics:

Answer 15

Wide inter and intra-subject variability
Unpredictable pharmacokinetics and pharmacodynamics
Various drug interactions

Question 16

Major Factors affecting CNI/TORI Pharmacokinetics

Answer 16

Genetics (CYP3A4, CYP3A5, MDR1,and ethnicity etc)
Age
Liver Function
Concurrent medications
Food Intake (contents, timing, etc)
Time after transplantation

Question 17

Minor Factors affecting CNI/TORI Pharmacokinetics

Answer 17

Time of administration (circadian variation)
Formulation
Gender
Obesity
Hematocrit/Lipoprotein

Question 18

What are the known isoenzymes

Answer 18

CYP3A4, CYP3A5, CYP3A7, AND CYP3A43

Question 19

CYP3A7

Answer 19

mainly expressed in fetal liver

Not detected in most adults’ liver after birth

Question 20

CYP3A43

Answer 20

Recently identified
Low expression in the liver
Functional significance is unknown

Question 21

CYP3A4 gene

Answer 21

major P450 enzyme in the liver and GI tract
It contains 13 exons
A total of 19 polymorphisms identified

Question 22

CYP3A4 *22 allele

Answer 22

Intron 6 SNP
Affects mRNA expression 2-5 fold
Decreases statin dose requirements

Question 23

CYP3A422-CYP3A5*3

Answer 23

gene-gene interactions

Question 24

CYP3A5 Polymorphism

Answer 24

A total of 13 exons
CYP3A51: full length CYP3A5 mRNA and express CYP3A5
CYP3A53 (22839 A to G): an abnormally spliced mRNA
CYP3A5*6 (30597 G to A): delete exon 7

Question 25

Functional wild type allele frequency of CYP3A5

Answer 25

Caucasians: 5-15% Japanese: 15-30% African Americans: 45-73% Southwestern American Indians: 60%

Question 26

Where is P-glycoprotein and MDR1 gene located?

Answer 26

Located in the long arm of chromosome 7

Question 27

P-glycoprotein and MDR1 Gene

Answer 27

Core promoter region and 28 exons It encodes for P=glycoprotein (P-gp), 170 kDa membrane transport glycoprotein P-gp acts as an ATP-dependent efflux pump P-glycoprotein- an ATP-binding cassette superfamily of transport proteins

Question 28

What type of pump is P-gp?

Answer 28

Efflux pump

Question 29

High Pgp

Answer 29

lower CYP3A activity

Question 30

Polymorphism of MDR1 gene

Answer 30

15 polymorphisms identified | Among these, 12 do not alter the protein sequence