| Indication |
For the palliative treatment of multiple myeloma and for the
palliation of non-resectable epithelial carcinoma of the ovary. Has also
been used alone or as part of various chemotherapeutic regimens as an
adjunct to surgery in the treatment of breast cancer, alone or in
combination regimens for palliative treatment of locally recurrent or
unresectable in-transit metastatic melanoma of the extremities, as well
as for the treatment of amyloidosis with prednisone. |
| Pharmacodynamics |
Melphalan is an antineoplastic in the class of alkylating agents
and is used to treat various forms of cancer. Alkylating agents are so
named because of their ability to add alkyl groups to many
electronegative groups under conditions present in cells. They stop
tumor growth by cross-linking guanine bases in DNA double-helix strands -
directly attacking DNA. This makes the strands unable to uncoil and
separate. As this is necessary in DNA replication, the cells can no
longer divide. In addition, these drugs add methyl or other alkyl groups
onto molecules where they do not belong which in turn inhibits their
correct utilization by base pairing and causes a miscoding of DNA.
Alkylating agents are cell cycle-nonspecific. Alkylating agents work by
three different mechanisms all of which achieve the same end result -
disruption of DNA function and cell death. |
| Mechanism of action |
Alkylating agents work by three different mechanisms: 1)
attachment of alkyl groups to DNA bases (primarily at the N-7 position
of guanine and to a lesser extent, at the N-3 position of adenine),
forming monoadducts and resulting in the DNA being fragmented by repair
enzymes in their attempts to replace the alkylated bases, preventing DNA
synthesis and RNA transcription from the affected DNA, 2) DNA damage
via the formation of cross-links (bonds between atoms in the DNA) which
prevents DNA from being separated for synthesis or transcription, and 3)
the induction of mispairing of the nucleotides leading to mutations. |
| Absorption |
Incomplete, variable, 25-89% post oral dose |
| Volume of distribution |
|
| Protein binding |
Moderate to high (60 to 90%), primarily to albumin and, to a
lesser extent, alpha 1-acid glycoprotein. 30% is irreversibly bound. |
| Metabolism |
Melphalan is not actively metabolised, it spontaneously degrades to mono and dihydroxy products. |
| Route of elimination |
The 24-hour urinary excretion of parent drug in these patients was
10% ± 4.5%, suggesting that renal clearance is not a major route of
elimination of parent drug. |
| Half life |
1.5 (±0.83) hours |
| Clearance |
Not Available |
| Toxicity |
Vomiting, ulceration of the mouth, diarrhea, and hemorrhage of the
gastrointestinal tract; The principal toxic effect is bone marrow
suppression. LD50=11.2 mg/kg (orally in rat) |
