Bioavailability and toxicity after oral administration of m-iodobenzylguanidine (MIBG)

Abstract

Summary meta-iodobenzylguanidine (MIBG) radiolabelled with iodine-131 is used for diagnosis and treatment of neuroadrenergic neoplasms such as phaeochromocytoma and neuroblastoma. In addition, non-radiolabelled MIBG, administered i.v., is used in several clinical studies. These include palliation of the carcinoid syndrome, in which MIBG proved to be effective in 60% of the patients. Oral MIBG administration might be convenient to maintain palliation and possibly improve the percentage of responders. We have, therefore, investigated the feasibility of oral administration of MIBG in an animal model. Orally administered MIBG demonstrated a bioavailability of 59%, with a maximal tolerated dose of 60 mg kg -1 . The first and only toxicity encountered was a decrease in renal function, measured by a reduced clearance of [ 51 Cr]EDTA and accompanied by histological tubular damage. Repeated MIBG administration of 40 mg kg -1 for 5 sequential days or of 20 mg kg -1 for two courses of 5 sequential days with a 2-day interval did not affect renal clearance and was not accompanied by histological abnormalities in kidney, stomach, intestines, liver, heart, lungs, thymus, salivary glands and testes. Because of a sufficient bioavailability in absence of gastrointestinal toxicity, MIBG is considered suitable for further clinical investigation of repeated oral administration in patients.

Endovascular hypothermia in the setting of myocardial infarction complicated by cardiac arrest: A case report

“…Intravenously administered, nonradiolabeled MIBG is generally well tolerated at doses as high as 8.5–40 mg/m 2,9 which correspond well with the concentrations used in our study; possible side effects of MIBG therapy include mild and transient changes in blood pressure; bone marrow suppression and thrombocytopenia were not seen 8. Oral administration of cold MIBG has been shown to have a bioavailability of 59 %, with a maximal tolerated dose of 60 mg/kg 30. Even at such high doses, no severe side effects or gastrointestinal toxicity were observed after oral administration.…”

Meta‐iodobenzylguanidine induces growth inhibition and apoptosis of neuroendocrine gastrointestinal tumor cells

“…8 Oral administration of cold MIBG has been shown to have a bioavailability of 59 %, with a maximal tolerated dose of 60 mg/kg. 30 Even at such high doses, no severe side effects or gastrointestinal toxicity were observed after oral administration. Thus, orally administered cold MIBG may provide a simple treatment option, especially in elderly patients or those in poor condition, and without the need of isolation.…”

pH‐dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2‐bis(methylsulfonyl)‐1‐(2‐chloroethyl)hydrazine prodrugs

“…Prodrugs containing acyl and alkoxycarbonyl masking groups do not undergo spontaneous masking group cleavage at any significant rate at close to neutral pH values and are activated by metabolic processes, while the alkylaminocarbonyl masking groups readily undergo spontaneous base catalyzed elimination/cleavage [4][5][6]15,16] (Figure 1 panel a). The atypically alkaline intracellular pH (pHi) values of ~7.5 to 7.65 commonly found in tumor cells [35,36] (Figure 1 panel d), including L1210 leukemia, [37] compared to those of normal tissue cells (pH value of ~7.2) [35] could potentially speed the base catalyzed activation of alkylaminocarbonyl prodrugs.…”