Renal toxicity of the neuron-blocking and mitochondriotropic agent m -iodobenzylguanidine

Abstract

meta-Iodobenzylguanidine (MIBG) is a multipotent drug used in its radiolabeled form as a tumor-seeking radiopharmaceutical in the diagnosis and treatment of pheochromocytoma and neuroblastoma. Nonradiolabeled MIBG has also proved to be effective in the palliation of carcinoid syndromes and, on a predosing schedule, in enhancing the relative tumor uptake of a subsequent [131I]-MIBG dose in tumors of neuroadrenergic origin. In addition, MIBG is under investigation as an inhibitor of mitochondrial respiration and, as such, for its use in tumor-specific acidification. In this report we describe the side effects of nonradiolabeled MIBG on kidney function in mice. High doses of MIBG (40 mg/kg) reduced renal blood perfusion as measured by 86Rb distribution by 50%, which could be antagonized by the bioamine receptor blockers prazosin and cyproheptadine. MIBG also induced reversible renal damage as evidenced from a decrease in [51Cr]-ethylenediaminetetraacetic acid (EDTA) clearance and from histological damage, which was most pronounced in the distal tubuli. These effects were unrelated to reduced perfusion, however, and could not be antagonized by bioamine receptor blockers, Ca2+-channel blockers, or diuretics. Clearance effects of MIBG were mimicked by N-nitro-L-arginine methyl ester (L-NAME), a known inhibitor of nitric oxide synthase (NOS), and MIBG itself (100 microM) also inhibited NOS in vitro, suggesting that NOS inhibition by MIBG may have contributed to the observed reduction in renal clearance. The MIBG analog benzylguanidine (BG), which is equipotent in terms of mitochondrial inhibition, did not affect renal clearance, thus excluding mitochondrial inhibition as the main mechanism of MIBG-induced damage. MIBG, however, was much more cytotoxic than BG to kidney tubular cells in primary cultures. Although the renal effects of high-dose MIBG were reversible, alterations in the pharmacokinetics of concomitant medications by a temporary reduction in renal function should be taken into account in its clinical application.

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

“…Renal damage was observed by histological analysis 5 and 24 h after treatment with 50 and 60 mg kg -1 and had recovered after 7 days, similar to what was described for i.p.-administered MIBG (Kuin et al, 1998). The damage was observed as acute degeneration and vacuolization of renal epithelial cells of the corticomedullar tubules, dilatation, most prominent in the distal tubuli, and minor hypertrophy of the epithelium of Bowman's capsule.…”

“…These results were similar to those of previous studies demonstrating renal toxicity after i.p. administration of high-dose MIBG, most probably because of the direct toxic effects of MIBG, present in high concentrations in the primary urine (Kuin et al, 1998). In contrast, repeated oral administration of MIBG up to accumulated doses of 200 mg kg -1 did not induce histological damage of the kidney or other tissues.…”

“…Renal function was measured by determination of the glomerular filtration of [ 51 Cr]EDTA as described previously (Kuin et al, 1998). In short, [ 51 Cr]EDTA (0.37 MBq 100 µl -1 , specific activity 37-74 MBq mg -1 ; Amersham International, UK) was injected 4.5 h after single dose MIBG or 1 day after repeated MIBG administration.…”

“…However, contributions of mitochondrial inhibition by MIBG observed in vitro (Loesberg et al, 1990a) and in vivo (Kuin et al, 1994), vascular effects by inhibition of nitric oxide synthase (NOS) (Kuin et al, 1998) or interference with mono(ADP)ribosylation (Loesberg et al, 1990b), cannot be excluded.…”

“…Side-effects encountered above 30 mg kg -1 i.p. are stress-related, sympathomimetic effects, plausibly explained by the release of bioamines from their storage granules (Kuin et al, 1994), and reduced renal clearance rates accompanied by histological tubular damage (Kuin et al, 1998).…”