Chemical formula: C₁₃H₁₈Cl₂N₂O₂ Molecular mass: 305.2 g/mol PubChem compound: 460612
Melphalan is a bifunctional alkylating agent that prevents the separation and replication of DNA. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking the two DNA strands and thereby preventing cell replication.
The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the medicinal product in plasma and peak plasma concentration.
In studies of the absolute bioavailability of melphalan, the mean absolute bioavailability ranged from 56 to 85%.
Intravenous administration can be used to avoid variability in absorption associated with myeloablative treatment.
In a study of 18 patients administered melphalan 0.2 to 0.25 mg/kg bodyweight orally, a maximum plasma concentration (range 87 to 350 nanograms/ml) was reached within 0.5 to 2.0 h.
The administration of melphalan tablets immediately after food delayed the time to achieving peak plasma concentrations and reduced the area under the plasma concentration-time curves by between 39 and 45%.
Melphalan is distributed in most tissues of the body. It is moderately bound to plasma proteins with reported binding ranging from 69% to 78%. There is evidence that the protein binding is linear in the range of plasma concentrations usually achieved in standard dose therapy, but that the binding may become concentration-dependent at the concentrations observed in high-dose therapy. Serum albumin is the major binding protein, accounting for about 55 to 60% the binding, and 20% is bound to α1-acid glycoprotein. In addition, melphalan binding studies have revealed the existence of an irreversible component attributable to the alkylation reaction with plasma proteins.
In 28 patients with various malignancies who were given doses between 70 and 200 mg/m² body surface area as a 2 to 20 min infusion, the mean volumes of distribution at steady state and central compartment were, respectively, 40.2 ± 18.3 litres and 18.2 ± 11.7 litres.
Melphalan displays limited penetration of the blood-brain barrier. Several investigators have sampled cerebrospinal fluid and found no measurable medicinal product. Low cerebrospinal fluid concentrations (~10% of that in plasma) were observed in a single high-dose study in children.
The chemical hydrolysis of melphalan to monohydroxymelphalan and dihydroxy melphalan is the most important metabolic route in humans. These metabolites are inactive.
In vivo and in vitro data suggest that spontaneous degradation rather than enzymatic metabolism is the major determinant of the medicinal product's half-life in man.
In 15 children and 11 adults given high-dose intravenous melphalan (140 mg/m² body surface area) with forced diuresis, the mean initial and terminal half-lives were found to be 6.5 ± 3.6 min and 41.4 ± 16.5 min, respectively. Mean initial and terminal half-lives of 8.8 ± 6.6 min and 73.1 ± 45.9 min, respectively, were recorded in 28 patients with various malignancies who were given doses of between 70 and 200 mg/m² body surface area as a 2 to 20 min infusion. The mean clearance was 564.6 ± 159.1 ml/min.
In 13 patients given oral melphalan at 0.6 mg/kg bodyweight, the plasma mean terminal elimination half-life was 90 ± 57 min with 11% of the drug being recovered in the urine over 24 h. In 18 patients administered melphalan 0.2 to 0.25 mg/kg bodyweight orally, the mean elimination half-life was 1.12 ± 0.15 h.
Melphalan clearance may be decreased in renal impairment.
No correlation has been shown between age and melphalan clearance or with melphalan terminal elimination half-life.
Melphalan was mutagenic in Salmonella typhimurium. Melphalan caused chromosomal aberrations in vitro (mammalian cells) and in vivo (rodents).
Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic. There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer.
The potential therapeutic benefit when considering the use of melphalan must be balanced against the risk that may occur.
Melphalan was teratogenic in rats after single dose exposure in reproductive toxicity studies. In repeated dose reproductive toxicity studies, melphalan was maternal toxic and induced congenital malformations.
A single dose of melphalan in male mice induced cytotoxicity and chromosomal aberrations in sperm cells. In female mice a reduction in number of pups per litter was observed. After recovery, the number of pups per litter was also reduced over time, which was related to a reduced number of follicles.
In mice, melphalan administered intraperitoneally at a dose of 7.5 mg/kg, showed reproductive effects attributable to cytotoxicity in specific male germ cell stages and induced dominant lethal mutations and heritable translocations in post-meiotic germ cells, particularly in mid to late stage spermatids.
A study was performed to measure the total reproductive capacity of melphalan in female mice. Females received a single intraperitoneal dose of 7.5 mg/kg melphalan and were then housed with an untreated male for most of their reproductive life span (a minimum of 347 days post-treatment). A pronounced reduction in litter size occurred within the first post-treatment interval, followed by an almost complete recovery. Thereafter, a gradual decline in litter size occurred. This was simultaneous with a reduction in the proportion of productive females, a finding associated with an induced reduction in the number of small follicles.
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