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Figure 1. Bendamustine structure
(Figure omitted. See article PDF.)
Figure 2. Bendamustine metabolism. Modified from [10].
(Figure omitted. See article PDF.)
Bendamustine hydrochloride was first synthesized in 1963 in the former East German Democratic Republic by Ozegowski et al. [1]. For over 30 years, bendamustine was used as monotherapy in various hematological malignancies and breast cancer. Unfortunately, few validated study results exist from this early period. Following the German reunification, bendamustine was approved in this country for the treatment of patients with indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and metastatic breast cancer. In the USA, bendamustine is approved for the treatment of patients with CLL and, more recently, for the treatment of patients with indolent B-cell NHL with progressive disease (PD) during or within 6 months from discontinuation of treatment with rituximab or a rituximab-containing regimen.
Bendamustine is a cytostatic drug and structurally comprises of three elements: a 2-chloroethylamine alkylating group, a benzimidazole ring and a butyric acid side chain (Figure 1). The 2-chloroethylamine alkylating group is shared with other members of the nitrogen mustard family of alkylators, which includes cyclophosphamide, chlorambucil and melphalan, and the butyric acid side chain is shared with chlorambucil. The benzimidazole central-ring system is unique to bendamustine; the intent of adding this structure to the nitrogen mustard was to include the antimetabolite properties shown for benzimidazole [2,3]. This heterocyclic ring structure may contribute to the unique antitumor activity of bendamustine and distinguish it from conventional 2-chloroethylamine alkylators [4].
Alone, as well as in combination with several anticancer drugs, bendamustine exhibited efficacy in the treatment of several malignancies, including lymphoproliferative disorders and solid tumors, particularly breast cancer.
The current review brings together knowledge of the pharmacokinetics, mechanisms of action and clinical use of bendamustine in lymphoproliferative disorders.
Metabolism
Bendamustine undergoes extensive first-pass metabolism, primarily in the human hepatic microsomes by the action of cytochrome P450 enzyme complex. However, unmetabolized drug accounts for approximately 45% of the total drug recovered in urine. Metabolites included the major metabolite β-hydroxybendamustine (which is also cytotoxic) and other hydroxy derivatives and N-dimethylbendamustine. Biliary metabolism may lead to some polar and apolar metabolites, although this is a minor route of metabolism (Figure 2) [5,6].
Following intravenous administration, a high percentage (>95%)...