Antimetabolites Flashcards
3 types of antimetabolites
Folate analogs
Pyrimidine analogs
Purine analogs
Folate analogs [drug names]
Methotrexate
Pemetrexed
Pralatrexate
Pyrimidine analogs [drug names]
Fluorouracil
Capecitabine
Cytarabine
Gemcitabine
Purine analogs [drug names]
Thioguanine Mercaptopurine Fludarabine Cladribine Pentostatin
What form of folate is essential in humans?
Tetrahydrofolate
Folate analogs [MOA]
inhibition of dihydrofolate reductase (DHFR is enzyme that turns folic acid to dihydrofolate and then to tetrahydrofolate)
inhibition of thymidylate synthase
Folate analogs [PK]
Lipophobic –> will not cross BBB
Renally eliminated
Folate analogs [DDIs]
anything that reduces renal blood flow – NSAIDs, nephrotoxic drugs, cisplatin
Folate analogs [ADEs]
methotrexate – mucositis and myelosuppresion
pregnancy category X
Folate analogs [Treating ADEs]
Folinic Acid [Leucovorin]
Fully reduced folate coenzyme; will decrease MOA so avoid if possible
Reverses myelosuppression & mucositis caused by methotrexate because substitutes for 5,10-methylene-THF
Folate analogs [Mechanisms of Resistance]
SLC19A1 mutations [brings methotrexate INTO cell]
DHFR mutations [alters binding affinity of drug and increased expression of DHFR]
Folylpolyglutamate synthetase mutations
Increased expression of efflux transporters (ABCs)
Enhanced expression of thymidylate synthase
Folate analogs [PGx]
SLC19A1 allows entrance of methotrexate INTO cell
Amplification = more drug to cell
How many times are folate metabolites used to transfer methyl groups in nucleic acid synthesis?
purines: 2
pyrimidines: 1
What is the result of polyglutamylation of methotrexate?
More like to stay INSIDE cell
More likely to inhibit thymidylate synthase
Why is leucovorin used to treat methotrexate toxicity?
ENHANCES thymidylate synthase activity –> substitutes cofactor
Pyrimidine Analogs [subcategories]
Thymidylate Analogs
Fluoropyrimidine Analogs
Thymidylate analogs [MOA]
dUMP —> dTMP
enzyme: Thymidylate Synthase
cofactor: 5,10-methyl THF
donate methyl group from 5,10-methyl THF to dUMP to get dTMP
Thymidylate analogs [drug names]
Capecitabine
5-Fluorouracil [5-FU]
**Capecitabine is a prodrug that is converted to 5-FU
Fluoropyrimidine analogs [MOA]
Inhibition of thymidylate synthase
Inhibition of RNA processing
Incorporation into DNA (rare but still happens)
Fluoropyrimidine analogs [PK]
give IV because these drugs are orally unpredictable
Fluoropyrimidine analogs [Metabolism]
Metabolized by LIVER
Mediated by DPD (dihydropyrimidine dehydrogenase)
**MORE clearance = LESS adverse effects; inactive DPD–> MORE risk of adverse effects
Fluoropyrimidine analogs [ADEs]
Capecitabine and 5-FU: myelosuppression, mucositis, hand & foot syndrome (swelling/pain)
5-FU only: diarrhea
Fluoropyrimidine analogs [Mechanisms of Resistance]
Mutations in activating enzymes (b/c PRODRUGS)
Mutations in thymidylate synthase
Insufficient 5,10-methylenetetrahydrofolate (cofactor–> cannot form inhibitory complex; can add leucovorin to enhance 5-FU efficacy)
Leucovorin
Folinic Acid
Will REVERSE methotrexate toxicity
Will ENHANCE fluoropyrimidine analog activity
How does leucovorin enhance 5-FU activity?
Can substitute as 5,10-methylene-THF and act as a cofactor to form inhibitory complex if insufficient amount available
Cytidine Analogs [drugs]
Cytarabine
Gemcitabine
Cytarabine [MOA]
due to trans -OH substituted for cis form, competes with dCTP for incorporation and causes DNA polymerase to be unable to synthesize more DNA
enters cell via hENT1 (nucleoside transporter)
converted Ara-C to Ara-CMP by enzyme deoxycytidine kinase (CdK)
Gemcitabine [MOA]
gemcitabine –> FdCMP via CdK
FdCDP inhibits ribonucleotide reductase (RNR)
FdCTP competes with dCTP for incorporation and stop DNA polymerase
Cytidine analogs [PK]
GIVE IV –> cytidine deaminase is high in GI tract; this enzyme degrades the drug; will not work as well
Cytidine analogs [ADEs]
Cytarabine and Gemcitabine: myelosuppression
Cytarabine ONLY: mucositis, hand & foot syndrome, visual disturbances
Cytidine analogs [Mechanisms of Resistance]
Loss of function deoxycytidine kinase (CdK)
Increased expression of cytidine deaminase or dCMP deaminase (metabolizes to non-toxic metabolites/degrades drug)
Mutations in hENT1 (helps drug enter cell )
Which folate metabolite is responsible for transfer of methyl group resulting in dUMP —> dTMP
5,10-methylene THF
Purine analogs [drug names]
Thioguanine
Mercaptopurine
Fludarabine
Cladribine
Thioguanine [MOA]
thioguanine –> 6-thioGMP via hypoxanthine guanine phosphoribosyl transferase (HGPRT) which
inhibits IMP dehydrogenase, which is the RLS of GTP synthesis–> loss of GTP pools, causing DNA damage
Mercaptopurine [MOA]
marcaptopurine –> 6-thioIMP via HGPRT, which inhibits PRPP glutamyl amidotransferase de novo purine synthesis; deplete ALL purine pools
Thiopurine methyltransferase (TPMT) and thiopurines
TPMT is the inactivating enzyme – low [TPMT] = high [drug] = increased ADE
6-thiopurines [Mechanisms of Resistance]
Loss of HGPRT function
Decreased drug uptake or increased efflux
Impaired recognition of DNA breaks
Impaired mismatch repair machinery
Adenine analogs [drug names]
Cladribine
Fludarabine
Fludarabine [MOA]
needs to be dephosphorylated to get INTO cell and then phosphorylated again once inside
inhibit DNA polymerase, DNA primase, DNA ligase and RNR
Cladribine [MOA]
inhibition of RNR
incorporation into DNA –> strand breaks
Adenosine Deaminase
Fludarabine and Cladribine are resistant to adenosine deaminase metabolism due to Cl and F groups on purine ring
