Topoisomerase I Flashcards
Which of the following is a principle dose limiting side effect of irinotecan?
a. Pulmonary toxicity
b. Hand and foot syndrome
c. Acute diarrhea
d. Neutropenia
d. Neutropenia
The two principle DLT are delayed diarrhea and neutropenia.
Which of the following would increase the biologic effects of irinotecan?
a. Decreased expression of ABCB1.
b. Up regulation of carboxylesterases.
c. Increased activity of UDP-glucuronosyl transferase.
d. Increased GFR.
B. Up regulation of carboxylesterases.
Irinotecan must be converted by a carboxylesterase-converting enzyme to active metabolite SN-38, which is responsible for its biologic effects. Inc levels of esterases ae assoc with inc sensitivity to irinotecan. UDP-glucuonosyl transferase converts SN-38 to SN-38 glucuronide (rate limiting step for elimination). SN-38G is inactive. Irinotecan is not a substrate for ABCB1. Irinotecan is eliminated via renal and biliary routes; therefore increasing excretion would not increase exposure time and biologic effect.
Which of the following is the principle form of Topotecan in plasma after IV administration?
a. Parent compound
b. Carboxylated form
c. Glucuronidated form
d. N-desmethyl metabolite
B. Carboxylated form
After IV administration, the lactone ring of topotecan undergoes rapid hydrolysis to generate the carboxylate species. The majority of the circulating drug in plasma is in the carboxylate form. N-desmethyl is a minor metabolite (possibly mediated by P450 enzymes). Topotecan and the main metabolite can undergo further metabolism into a UGT-mediated glucuronide product, but this is also a minor metabolite (takes place in the liver).
Which of the following limits the absorption of topotecan from the gastrointestinal system?
i. low pH within the small intestinal system causes increase of carboxylate form
ii. ABCB2 causes outward pumping of topotecan
iii. decreased bile salt secretion
iv. decomposition by gastrointestinal fluid
a. i, ii
b. ii, iv
c. iii, iv
d i, ii, iii
e. ii, iii, iv
D. low pH, ABCB2, decr bile salt
high pH is found in the small intestine with additional of sodium bicarbonate. This causes formation of the carboxylate form which is not readily absorbed
Which of the following drugs could enhance the activity of topotecan when administered together?
a. omeprazole b. dexamethasone c. levetiracetam d. l-asparaginase e. ketoconazole
E. ketoconazole
pediatric study indicates that the CYP3A is the level at which there are drug interactions
What is the active metabolite of irinotecan?
a. SN-38G b. SN-38 c. UGT1A1 d. irinotecan carboxylate e. SN-38 carboxylate
B. SN-38
Which of the following is true about the pharmacokinetics and metabolism of topotecan?
a. Multi-day CRIs result in a higher AUC compared to shorter infusions.
b. Topotecan lactone is rapidly converted to the carboxylate form in the stomach.
c. Topotecan is reformed in the intestines by β-glucuronidase.
d. Patients receiving phenobarbital are more likely to experience heightened toxicity from topotecan.
e. Topotecan undergoes extensive enterohepatic circulation.
C. Topotecan is reformed in the intestines by β-glucuronidase.
a. The short terminal half-life of topotecan lactone (2 to 3.5 hours) means that it does not accumulate when administered as a CRI.
b. Topotecan lactone is converted in the small intestine due to the high pH.
d. Inducers of cytochrome P-450 may enhance topotecan clearance.
e. This is just false. Topotecan is mainly excreted by the kidneys.
Which of the following drugs is NOT associated with activation to a cytotoxic metabolite?
a. Cyclophosphamide
b. Procarbazine
c. Topotecan
d. 5-Fluorouracil
e. Cytosine arabinoside
C. Topotecan
Topotecan is a topoisomerase I inhibitior that does not require activation.
Cyclophosphamide → phosphoramide mustard
Procarbazine → azoprocarbazine → benzylazoxyprocarbazine, methylazoxyprocarbazine
5-FU → FdUMP, FdUTP and FUTP
Cytosar → ara-CTP
Identify the site of hydrolysis on the topotecan molecule.
a. NH2 terminal domain
b. Lactone ring
c. NH4+
d. Chloroethyl group
e. Carboxyl group
b. Lactone ring
Which of the following patients should receive a reduced dose of topotecan?
i. A patient with mediastinal lymphoma who has received 2 prior fractions of radiation therapy
ii. A patient with azotemia and a specific gravity of 1.038
iii. A patient with a serum bilirubin of 11 mg/dl
iv. A patient with severe malassezia being treated with ketoconazole
v. A patient with an allergy to sulfa drugs
a. i, ii, and iv
b. iii and iv
c. ii, iii, and v
d. iii only
e. iv and v
b. serum bili 11, ketoconazole
Explanation: serum bilirubin >10 mg/dl and treatment with a CYP3A substrate are both reasons to consider dose reduction. Extensive RT and chemo may also require dose reductions.
Co-treatment with which of the following could theoretically decrease the GI toxicity associated with irinotecan?
a. prednisone
b. azathioprine
c. cyclosporine A
d. mycophenolate
c. cyclosporine A
By reducing bile flow and inhibiting bile canalicular active transport it can modulate SN-38-mediated toxicity
Which of the following could contribute to sensitivity to camptothecins?
i. more cells in S phase
ii. decreased repair of double strand breaks
iii. increased metallothionein concentrations
iv. increased expression of ABCB-1
a. i, iii
b. iii, iv
c. ii, iv
d. i, ii
d. more cells in S phase, decreased DSB repair
(iii) should cause resistance and (iv) should not affect sensitivity.
In regards to irinotecan, which of the following is believed to be predominately responsible for SN-38 metabolism in humans?
a. UGT1A1
b. UGA1T2
c. UGT1A8
d. UGT1A2
a. UGT1A1
p. 346 (Haas)
Identify the main mechanisms to which irinotecan treatment may be altered, meaning what are the pathways of resistance and/or sensitivities to the drug?
i. Point mutations of topoisomerase I associated with resistance
ii. Increased levels of esterases within the cell associated with increased sensitivity
iii. Overexpression BCL-2 and BCL-XL associated with resistance
iv. Reduction of the number of cells in the S phase associated with decreased sensitivity
a. iii
b. i, iii
c. i, ii, iii, iv
d. i, ii, iv
d. point mutations in topo I, increased esterases, reduction in # of cells in S phase
p. 347 (Haas)
Identify the advantages of liposomal and nano-particle encapsulated and carrier mediated drugs?
i. Decreased solubility
ii. Prolonged duration of exposure
iii. Improved therapeutic index
iv. Pharmacokinetic disposition of these agents is dependent on the parent drug
v. Overcoming resistance
a. iv
b. ii, iii, v
c. i, iv
d. i, ii, iv
b. prolonged exposure, improved ther index, overcoming resistance
p. 349 (Haas)
