Summary
Experiments to determine the hydrolysis and protein binding of melphalan (l-phenylalanine mustard, l-PAM) were carried out in vitro for therapeutic concentrations of the drug: the decrease in l-PAM concentration in plasma and whole blood during 24 h incubation at 37°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 α-acid 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 μg/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.
Similar content being viewed by others
References
Alberts DS, Chang SY, Chen H-SG, Moon TE, Evans TL, Furner RL, Himmelstein K, Gross JF (1979a) Kinetics of intravenous melphalan. Clin Pharmacol Ther 26: 73–80
Alberts DS, Chang SY, Chen H-SG, Evans TL, Moon TE (1979b) Oral melphalan kinetics. Clin Pharmacol Ther 26: 737–745
Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, Stuckey WJ, Wilson HE (1969) Treatment for multiple myeloma. J Am Med Assoc 208: 1680–1685
Begleiter A, Lam H-YP, Grover J, Froese E, Goldenberg GJ (1979) Evidence for active transport of melphalan by two amino acid carriers in L5178Y lymphoblasts in vitro. Cancer Research 39: 353–359
Chang SY, Alberts DS, Farquhar D, Melnick LR, Walson PD, Salmon SE (1978b) Hydrolysis and protein binding of melphalan. J Pharm Sci 67: 682–684
Chirigos MA, Mead JAR (1964) Experiments on determination of melphalan by fluorescence. Interaction with protein and various solutions. Anal Biochem 7: 259–268
Cohn P (1957) The distribution of radioactivity in tissues of the rat following the administration of a nitrogen mustard derivative. Br J Cancer 1: 258–267
Israili ZH, El-Attar H (1983) Binding of some acidic drugs to α-acid glycoprotein. Clin Pharmacol Ther 33: 255
Jusko WJ, Gretch M (1976) Plasma and tissue protein binding of drugs in pharmacokinetics. Drug Metabol Rev 5 (1): 43–140
Kurz H (1969) Einfluß der Proteinbinding auf die Verteilung von Arzneimitteln nach schneller und langsamer Injektion. Naunyn Schmiedeberg's Arch Pharmacol 263: 233
Loos U, Musch E, Engel M, Hartlapp JH, Hügl E, Dengler HJ (1987) Pharmacokinetics of melphalan during intermittent therapy of multiple myeloma. Submitted for publication Eur J Clin Pharmacol
Milner AN, Klatt O, Young SE, Stehlin JS, Jr (1965) The biochemical mechanism of action of 1-phenylalanine mustard, I. distribution of 1-phenylalanine mustard-h3 in tumor bearing rats. Cancer Res 25: 259–264
Ohnhaus EE (1979) Arzneimittelwechselwirkungen durch Beeinflussung der Plasmaeiweißbindung. Internist 20: 225–228
Osterheld HKO, Musch E, von Unruh GE, Loos U, Rauschecker H, Mühlenbruch BJ (1988) Sensitive high-performance liquid chromatographic assay for melphalan and its hydrolysis products in blood and plasma. Cancer Chemother Pharmacol 21: 156–162
Piafsky KM, Borga O (1977) Plasma protein binding of basic drugs: II. Importance of α-acid glycoprotein for interindividual variations. Clin Pharmacol Ther 22: 545–549
Tattersall MHN, Jarman M, Newlands ES, Holyhead L, Milstead RAV, Weinberg A (1978) Pharmaco-kinetics of melphalan following oral or intravenous administration in patients with malignant disease. Eur J Cancer 14: 507–513
Urien S, Albengres E, Zini R, Tillement JP (1982) Evidence for binding of certain acidic drugs to α-acid glycoprotein. Biochem Pharmacol 31: 3687–3689
Wilkinson GR (1983) Plasma and tissue binding considerations in drug disposition. Drug Metabol Rev 14 (3): 427–465
Author information
Authors and Affiliations
Additional information
Supported by the Ministry of Science and Research, Land Nordrhein-Westfalen, FRG
Rights and permissions
About this article
Cite this article
Gera, S., Musch, E., Osterheld, H.K.O. et al. Relevance of the hydrolysis and protein binding of melphalan to the treatment of multiple myeloma. Cancer Chemother. Pharmacol. 23, 76–80 (1989). https://doi.org/10.1007/BF00273521
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00273521