Drugs that disrupt DNA / Crosslinking agents / Pharmacokinetics
I. Crosslinking agents
Pharmacokinetics
One major distinguishing feature among alkylating agents is the rate at which the parent drug is converted to a strong electrophile. For some drugs (e.g. MECHLORETHAMINE), the reaction is virtually instantaneous --- these agents are given IV to minimize blistering and GI effects. Other agents (such as CYCLOPHOSPHAMIDE, BUSULFAN, and MELPHALAN) must be activated in various tissues, and they can be given orally. |
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MECHLORETHAMINE: instantaneous activation upon contact with water à vesicant (common toxicity of many cytotoxic agents)
CYCLOPHOSPHAMIDE:
- derivative of mechlorethamine that must be activated by liver CYP450 enzymes as the first step in a multistep activation process
- induction/inhibition of CYP2B6 by other drugs will have the opposite effect on CYCLOPHOSPHAMIDE than conventional drug/drug interactions (induction of the enzyme increases activity)
- final steps create the active drug (PHOSPHORAMIDE MUSTARD) plus ACROLEIN
- ACROLEIN is responsible for the unique toxicity associated with CYCLOPHOSPHAMIDE (hemorrhagic cystitis; because it is a byproduct, the acrolein can be removed by administering MESNA with no change in therapeutic effect)
