Oral alkylating agent with CNS penetration with activity with melanoma and gliomas.

A second generation oral alkylating agent.

Temodar trade name.

Methylates DNA.

Depletes cells of a DNA repair enzyme O-methylguanine-DNA methyltransferase (MGMT) which protects DNA removing alkyl groups from O position, allowing continuation of DNA replication.

MGMT can only remove one alkyl group per enzyme before it deactivates itself.

Acts by creating an excess of DNA adducts at the O position depleting MGMT.

Confers cytotoxic effect via formation of O6-methylguanine, which activates, and subsequently inhibits the cellular DNA mismatch repair mechanism, producing DNA mismatch repair mechanisms, inducing DNA double strand breaks, which induces apoptosis.

Converts to MTIC, the active metabolite of dacarbazine.

A prodrug.

Maximum plasma concentrations occur 30-90 minutes after oral intake with a plasma half life of approximately 2 hours.

CSF pharmokinetics compared with plasma has an area under the concentration time curve (AUC) of approximately 20% of the AUC.

Adverse reactions include thrombocytopenia, neutropenia, CD4 selective lymphocytopenia with increased risk of opportunistic infections, nausea,, constipation, peripheral edema, neuromuscular weakness, pharyngitis, sinusitis, cough, respiratory tract infections and dyspnea.

When concurrently given with radiation therapy can deplete CD4+ lymphocyte population.

Has better CNS penetration than dacarbazine in patients with metastatic disease.

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