A. Kuin et al., RENAL TOXICITY OF THE NEURON-BLOCKING AND MITOCHONDRIOTROPIC AGENT M-IODOBENZYLGUANIDINE, Cancer chemotherapy and pharmacology, 42(1), 1998, pp. 37-45
meta-Iodobenzylguanidine (MIBG) is a multipotent drug used in its radi
olabeled fc,rm 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 sy
ndromes and, on a predosing schedule, in enhancing the relative tumor
uptake of a subsequent [(131)]-MIBG dose in tumors of neuroadrenergic
origin. In addition, MIBG is under investigation as an inhibitor of mi
tochondrial respiration and, as such, for its use in tumor-specific ac
idification. In this report we describe the side effects of nonradiola
beled MIBG on kidney function in mice. High doses of MIBG (40 mg/kg) r
educed renal blood perfusion as measured by Rb-86 distribution by 50%,
which could be antagonized by the bioamine receptor blockers prazosin
and cyproheptadine. MIBG also induced reversible renal damage as evid
enced from a decrease in [Cr-51]-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 mi
micked by N-nitro-L-arginine methyl ester (L-NAME), a known inhibitor
of nitric oxide synthase (NOS), and MIBG itself (100 mu M) also inhibi
ted NOS in vitro, suggesting that NOS inhibition by MIBG may have cont
ributed to the observed reduction in renal clearance. The MIBG analog
benzylguanidine (BG), which is equipotent in terms of mitochondrial in
hibition, did not affect renal clearance, thus excluding mitochondrial
inhibition as the main mechanism of MIBG-induced damage. MIBG, howeve
r, 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.