Medical Pharmacology Chapter 33-34: Anticancer Drugs
Alkylating Agents (Continued):
Classification8
Ethyleneimes/Methylmelamines (continued)
Thiotepa
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Thiotepa is a tertiary aziridine compound exhibiting weak alkylating properties.23
However, the parent compound, thiotepa, can be activated following oxidative desulfuration, to form a cytotoxic metabolite, TEPA (triethylenephosphoramide).
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Both agents, thiotepa and TEPA appeared to alkylate DNA, a process associated with hydrolytic release of aziridine which is a target for DNA nucleophiles.23
Thiotepa, compared to TEPA, may be favored for regioselective DNA alkylation because of its reduced rate of intracellular hydrolysis.
TEPA, the desulfurated thiotepa metabolite, is the main drug species found in plasma shortly after (if you hours) of thiotepa administration.4
The plasma half-life (t˝) of thiotepa is about 1-2 hours. TEPA exhibits a longer t˝ of about 3-24 hours.
Conversion of thiotepa to TEPA is catalyzed by isoforms of the cytochrome P450 drug metabolizing system.4
After 24 hours only about 1%-2% of the parent drug, thiotepa, is excreted unchanged in the urine.
About 4% is excreted in the urine as TEPA and about 25% as numerous derivative alkylating metabolites.27
Sinusoidal obstruction syndrome (SOS) a.k.a. venoocclusive disease (VOD) of the liver may be observed in some patients receiving high-dose chemotherapy with thiotepa.
Nitrosoureas, busulfan, or carboplatin may also cause this significant and potentially fatal toxicity.
Mucositis and enterocolitis are also significant side effects of many higher dose chemotherapy protocols including those using thiotepa, melphalan and etoposide.27
High-dose chemotherapy may also manifest as a cutaneous toxicity involving rashes, more typically a "macular erythematous eruption."27
One study described as an observational pilot study considered 127 patients receiving high-dose chemotherapy.28
14 of these patients were found to develop maculopapular rashes.
Some rashes were described as mild, others as “scattered macular or maculopapular rashes” and still others as severe rashes.
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Some patients received a protocol including high-dose corticosteroids. Among patients receiving induction protocols utilizing cytarabine, about 50% of patients exhibited rashes.
However, no rashes were noted on patients receiving a protocol including high-dose corticosteroids.28
Thiotepa, nitrosoureas, and especially busulfan represent highly lipid-soluble alkylating drugs.27
As a result, these agents are more likely to enter the CNS and may cause a variety of CNS abnormalities. These abnormalities include seizures, cerebellar dysfunction, cranial nerve palsies, altered mental status and even coma.27
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