THIOGUANINE

Chemistry - A purine analog antineoplastic agent, thioguanine occurs as a pale yellow, odorless orpractically odorless, crystalline powder. It is insoluble in water or alcohol. Thioguanine may also beknown as 6- thioguanine, TG, 6-TG, or 2-Amino-6-mercaptopurine.

Storage, Stability, Compatibility

Store tablets in tight containers at room temperature.

Pharmacology - THIOGUANINE

Intracellularly, thioguanine is converted to ribonucleotides that cause the synthesisand utilization of purine nucleotides to be blocked. The drug's cytotoxic effects are believed tooccur when these substituted nucleotides are inserted into RNA and DNA. Thioguanine also haslimited immunosuppressive activity. Extensive cross-resistance usually occurs between thioguanineand mercaptopurine.

Uses, Indications

Thioguanine may be useful as adjunctive therapy for acute lymphocytic orgranulocytic leukemia in dogs or cats.

Pharmacokinetics - THIOGUANINE

Thioguanine is administered orally, but absorption is variable. In humans, only about 30% of a dose is absorbed. Thioguanine is distributed into the DNA and RNA of bonemarrow, but several doses may be necessary for this to occur. It does not apparently enter the CNS, but does cross the placenta. It is unknown whether it enters maternal milk.
Thioguanine is rapidly metabolized primarily in the liver to methylate derivative that is less active(and toxic) than the parent compound. This and other metabolites are then eliminated in the urine.

Contraindications, Precautions, Reproductive Safety

Thioguanine is contraindicated in patients hypersensitive to it. The drug should be used cautiously (risk versus benefit) in patients withhepatic dysfunction, bone marrow depression, infection, renal function impairment (adjust dosage)or have a history of urate urinary stones. Thioguanine has a very low therapeutic index and shouldonly be used by clinicians with experience in the use of cytotoxic agents and able to monitortherapy appropriately.
Thioguanine is potentially mutagenic and teratogenic and is not recommended for use duringpregnancy. Although it is unknown whether thioguanine enters milk, use of milk replacer is recommended for nursing bitches or queens.

Adverse Effects, Warnings

At usual doses, GI effects (nausea, anorexia, vomiting, diarrhea) mayoccur in small animals. However, bone marrow suppression, hepatotoxicity, pancreatitis, GI(including oral) ulceration, and dermatologic reactions are potentially possible. Cats may be particularly susceptible to the hematologic effects of thioguanine.
Overdosage, Acute Toxicity - Toxicity may present acutely (GI effects) or be delayed (bonemarrow depression, hepatotoxicity, gastroenteritis). It is suggested to use standard protocols toempty the GI tract if ingestion was recent and to treat supportively.

Drug Interactions

Use extreme caution when used concurrently with other drugs that are alsomyelosuppressive, including many of the other antineoplastics and other bone marrow depressant drugs (e.g., chloramphenicol, flucytosine, amphotericin B, or colchicine). Bonemarrow depression may be additive. Use with other immunosuppressant drugs (e.g., azathioprine, cyclophosphamide, corticosteroids) may increase the risk of infection. Live virus vaccines should be used with caution, if at all during therapy.
Thioguanine should be used cautiously with other drugs that can cause hepatotoxicity (e.g., halothane, ketoconazole, valproic acid, phenobarbital, primidone, etc.).
Laboratory Considerations - Thioguanine may increase serum uric acid levels in some patients.