The pharmacokinetics of melphalan during intermittent therapy of multiple myeloma

Loos, U.; Musch, E.; Engel, Martin; Jh, Hartlapp; Hugl, E; Hj, Dengler

doi:10.1007/bf00609251

Cited by 13 publications

(1 citation statement)

References 29 publications

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“…Since there is no appreciable active metabolism in vivo, it is possible that the increase in peak plasma level and area under the concentration/time curve (AUC) might be due to changes in drug transport. 23 In addition, absorption may be affected by food intake with a median reduction of AUC of 39% and a reduction in bioavailability from 85% to 58% when oral melphalan is administered after a meal. 24 After intravenous administration, melphalan rapidly disappears from the plasma and is distributed in whole body water (Vd = 0.66 L/kg).…”

Section: Absorption and Distributionmentioning

confidence: 99%

Melphalan hydrochloride for the treatment of multiple myeloma

Esma

Salvini

Troia

et al. 2017

Expert Opinion on Pharmacotherapy

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Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections. Melphalan, a nitrogen mustard, is an alkylating agent synthesized in 1953, and it has been used in multiple myeloma therapy for fifty years. Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment. Areas covered: This review focuses on available data about melphalan pharmacology and its role in clinical practice. Expert opinion: Melphalan remains crucial in therapy of multiple myeloma because of its good manageability, safety profile, efficacy, and economic sustainability. These characteristics make it pivotal also for new regimens in combination with novel agents.

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Section: Absorption and Distributionmentioning

confidence: 99%

Melphalan hydrochloride for the treatment of multiple myeloma

Esma

Salvini

Troia

et al. 2017

Expert Opinion on Pharmacotherapy

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Relevance of the hydrolysis and protein binding of melphalan to the treatment of multiple myeloma

Gera

Musch

Osterheld

et al. 1989

Cancer Chemother. Pharmacol.

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Experiments to determine the hydrolysis and protein binding of melphalan (L-phenylalanine mustard, L-PAM) were carried out in vitro for therapeutic concentration of the drug: the decrease in L-PAM concentration in plasma and whole blood during 24 h incubation at 37 degrees C was only 5% due to hydrolysis. Serum protein binding was about 90%, whereby 60% and 20% of this binding was due to interactions with albumin and acid alpha 1-glycoprotein, respectively. Immunoglobulins did not participate in the binding of L-PAM. The covalently bound part of L-PAM in serum was 30% in the concentration range of 1-30 micrograms/ml. The binding of dihydroxymelphalan (DOH) in serum did not exceed 20%. Glucocorticoids used in combination with L-PAM for treating multiple myeloma did not influence its protein binding. Our study with 35 sera from 15 patients with multiple myeloma shows that high levels of paraproteins do not increase but may decrease the binding of L-PAM, resulting in an elevated concentration of free drug.

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Glutathione depletion increases the cytotoxicity of melphalan to PC-3, an androgen-insensitive prostate cancer cell line

Canada

Herman

Kidd

et al. 1993

Cancer Chemother. Pharmacol.

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Prostate cancer that is androgen-insensitive is unresponsive to a wide spectrum of cytotoxic agents, including all of the alkylating agents. Since a major pathway for the detoxification of the alkylating agents is conjugation with glutathione (GSH), GSH depletion has proved to be effective as a technique to restore melphalan sensitivity in melphalan-resistant cancer cell lines. However, the effect of GSH depletion has not been widely studied in tumor cell lines that have not developed resistance due to previous exposure to alkylating agents. Thus, we decided to investigate GSH depletion as a technique to increase melphalan cytotoxicity to PC-3 cells, an androgen-insensitive prostate cancer line. After 2 and 6 h incubation with 0.25-5 microM melphalan, virtually no effect was observed on either clonogenic lethality or MTT viability until 5 microM exposures. A 24-h incubation of the cells with 100 microM buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, reduced the GSH content by 70%-75%. Following GSH depletion, an increase in clonogenic lethality and a decrease in MTT viability occurred after exposure to concentrations as low as 0.25 microM. The dose modification factor ranged from 2.9 after 2 h incubation to 4.5 at 6 h. These results provide support for additional studies in prostate cancer for further investigation of GSH depletion as a technique to induce sensitivity to alkylating agents in this chemotherapy-resistant tumor.

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The pharmacokinetics of melphalan during intermittent therapy of multiple myeloma

Cited by 13 publications

References 29 publications

Melphalan hydrochloride for the treatment of multiple myeloma

Melphalan hydrochloride for the treatment of multiple myeloma

Relevance of the hydrolysis and protein binding of melphalan to the treatment of multiple myeloma

Glutathione depletion increases the cytotoxicity of melphalan to PC-3, an androgen-insensitive prostate cancer cell line

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