Biotransformation

Question 1

what were listed as the 5 “most important” CYP enzymes

Answer 1

CYP2A2
CYP2A6
CYP2D6
CYP2E1
CYP3A4**

Question 2

what do P450s use to carry out oxidation of substrates

Answer 2

O2 and H+ from NADPH

Question 3

pseudocholinesterase metabolizes what drug

Answer 3

succinylcholine

depolarizing neuromuscular blocking drug

Question 4

N-acetyltransferase metabolizes what drugs

Answer 4

Isoniazid (anti-TB)
Hydralazine (anti-HTN)
Caffeine

Question 5

what type of genetic defects are associated with decreased N-acetyltransferase ability to metabolize drugs

Answer 5

autosomal recessive

Question 6

what other symptom is associated with N-acetyltransferase deficiency

Answer 6

hepatitis

Question 7

what CYP enzyme does grapefruit juice inhibit

Answer 7

CYP3A4

Question 8

CYP3A4 metabolizes what types of drugs (5)

Answer 8

• anti-hypertensives
• immunosuppressants
• anti-depressants
• anti-histamines
• statins

Question 9

how does allopurinol affect metabolization of Mercaptopurine and what is the result

Answer 9

it inhibits xanthine oxidase which is what metabolizes mercaptopurine (an immunosuppressant in cancer patients) which prolongs duration of the drug and enhances its chemotherapeutic and toxic effects

Question 10

why does acetaminophen toxicity occur

Answer 10

too much acetaminophen causes hepatic GSH to deplete faster, so toxic metabolites accumulate resulting in hepatotoxicity

Question 11

polymorphisms in CYP2D6 cause what

Answer 11

insufficient pain relief and increased side effects of codeine
(CYP2D6 is what metabolizes codeine into morphine)

Question 12

polymorphisms in CYP2C19 cause what

Answer 12

increased risk of serious adverse CV events

CYP2C19 is what metabolizes clopidogrel to the active thiol metabolite form for anti-platelet activity

Question 13

28/28 allele genotype in the UGT1A1 enzyme causes what disease

Answer 13

Gilbert’s syndrome (60-70% increase in unconjugated bilirubin)
- UGT1A1 conjugates glucoronic acid onto bilirubin for bile excretion

Question 14

polymorphic UGT1A1 (not the 28/28 allele genotype) disrupts what biotransformational process

Answer 14

the hydrolization of ironotecan into SN-38 which blocks topoisomerase I, causing the termination of DNA replication and cell death (chemotherapy)

Question 15

polymorphic UGT1A1 (not the 28/28 allele genotype) causes what sx

Answer 15

• neutropenia
• diarrhea
• decreased clearance of SN-38 metabolite

Question 16

how does the enzyme TPMT affect Thiopurine drugs (immunosuppressants)

Answer 16

blocks 6-MP and 6-TG (thiopurine drugs) which decreases their therapeutic efficacy but also their bone marrow toxicity
- major determinant of thiopurine metabolism and exposure to cytotoxic 6-TGN metabolites and thiopurine-related toxicities

Question 17

how does a G6PD deficiency cause problems when using the drug Rasburicase

Answer 17

G6PD is the exclusive source of glutathione in RBCs, and glutathione is needed to reduce the H202 formed when Rasburicase converts uric acid into allantoin. A G6PD deficiency with use of Rasburicase causes hemolytic anemia and methemoglobinemia

Question 18

how does a reduced function polymorphism in the SLCO1B1 gene affect the uptake of statins

Answer 18

SLCO1B1 encodes the transporter OATP1B1 on the sinusoidal membrane of hepatocytes which controls uptake of statins, so the polymorphism decreases uptake of statins

Question 19

how does the rs4149056 polymorphism of SLCO1B1 affect use of simvastatin

Answer 19

the polymorphism increases systemic exposure of simvastatin which causes simvastatin-induced myopathy

Question 20

how do statins normally function

Answer 20

reduce serum lipids and prevent cardiovascular events

Question 21

what is the normal function of CYP2C9

Answer 21

interacts with microsomal P450 oxidoreductase which metabolizes S-warfarin, which targets VKORC1, a key enzyme in the vitamin K recycling process

Question 22

how do CYP2C92 and CYP2C93 affect metabolism of warfarin

Answer 22

they block interaction of CYP2C9 and microsomal P450 oxidoreductase, decreasing metabolism of warfarin

Question 23

what symptoms do genetic variants of VKORC1 cause

Answer 23

may lead to bleeding disorders, eg, multiple coagulation factor deficiency type 2A, or warfarin resistance

Question 24

how does the VKORC1-1639G>A polymorphism of VKORC1 affect sensitivity of warfarin

Answer 24

results in reduced expression of VKORC1 in the liver –> increased sensitivity to warfarin