Temozolamide

Temozolamide Barbara J. Rider Tulane Health Sciences Center, New Orleans, USA ã 2007 Elsevier Inc. All rights reserved.

Introduction Temozolamide, a prodrug, is an imidazotetrazine analog that undergoes spontaneous activation in solution to produce 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), a triazine derivative. It crosses the blood-brain barrier with concentrations in the central nervous system approximating 30% of plasma concentrations Agarwala and Kirkwood (2000). Temozolamide is effective in the treatment of gliomas and melanomas.

Nomenclature Name of the Clinical Form Related Names Source: EMTREE Chemical Names

Temozolamide Temodar; temozolomide, methazolastone; 3-Methyl-4-oxo3,4-dihydro-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amide 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8carboxamide; 8-carbamoyl-3-methylimidazo[5,1-d]1,2,3,5-tetrazin-4(3H)-one.

CAS Number

Basic Chemistry Chemical Structure Structure

Comments Chemical Formula Properties Physical Properties Molecular Weight Solubility

Temozolamide is an imidazotetrazine derivative. C6 H6 N6 O2

Temozolamide is a white to light tan or light pink powder with a melting point of 212 C. It is stable at pH <5 and labile at pH >7 Sifton (2002), Budavari (1996). 194.153

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Temozolamide

Human Pharmacokinetics Temozolamide is rapidly and completely absorbed following oral administration and is hydrolyzed to MTIC at physiological pH. MTIC is further converted to 5-aminoimidazole4-carboxamide (AIC) and methyl hydrazine. Cytochrome P450 enzymes play only a minor role in this activation process. Food reduces the absorption of temozolamide. Peak plasma levels are attained within 1 hour of oral administration, and the elimination half-life of temozolamide is approximately 1.8 hours. About 38% of an administered dose is recovered after 7 days Sifton (2002).

Pharmacokinetic Properties

Absorption Bioavailability Distribution Volume of Distribution Plasma Protein Binding Metabolism Plasma Half-Life Bio Half-Life Clearance Routes of Elimination

Value

Units

Prep. and Route of Admin.

100

%

p.o.

Friedman et al (2000)

0.4 15

l/kg %

p.o. p.o.

Sifton (2002) Sifton (2002)

1.8

hrs

p.o.

Sifton (2002)

Reference

Comments

5.5 l/hr/m2 p.o Sifton (2002) Temozolamide and its metabolites are excreted in the urine and feces.

Targets-Pharmacodynamics Temozolamide is nonenzymatically converted to MTIC, a triazine analog. MTIC is then converted to AIC and methylhydrazine. Methylhydrazine alkylates DNA primarily at the O6 and N7 positions at the guanine residues.

Target Name(s): DNA

Therapeutics Temozolamide is used for the treatment of certain types of brain tumors, especially refractory anaplastic astrocytoma Sifton (2002). It is used for the treatment of highgrade malignant gliomas and has demonstrated promising activity not only against brain tumors, but against a variety of solid tumors, including malignant melanoma Agarwala and Kirkwood (2000).

Temozolamide

Indications

Cancer Dosage

Value

Units

Prep. and Route of Admin.

150

mg/m2

p.o.

Reference

Comments

Sifton (2002)

Dose may be adjusted on the basis of blood counts.

Contraindications Temozolamide is contraindicated in those known to be hypersensitive to it. Adverse Effects Adverse effects associated with the use of temozolamide include nausea, vomiting, headache, fatigue, and myelosuppression, especially thrombocytopenia and neutropenia. Agent-Agent Interactions Agent Name

Mode of Interaction

Valproic acid

Valproic acid decreases the clearance of temozolamide.

Journal Citations Friedman, H.S., Kerby, T., Calvert, H., 2000. Temozolomide and treatment of malignant glioma. Clin. Cancer Res., 6(7), 2585–2597. Agarwala, S.S., Kirkwood, J.M., 2000. Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncologist, 5(2), 144–151.

Book Citations Sifton, D.W., 2002. Temodar. Sifton, D.W. (Ed.), Physicians’ Desk Reference, Edition 56, pp. 3157–3160, Medical Economics Company, Montvale, New Jersey. Budavari, S., 1996. Temozolomide. Budavari, S. (Ed.), The Merck Index, Edition 12, p. 1562, Merck and Co., Inc., Rahway, NJ.

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