Disposition of radioiodinated benzylguanidines in perfused rabbit lung: pharmacokinetics and effect of an organo-gold complexed antineoplastic agent.
SK&F 104524 (bis-[1,2-bis(diphenylphosphino)-ethane]-gold(I)-lactate) ([Au(dppe)2]+) is a lipophilic phosphine-coordinated gold complex that has significant antineoplastic activity. However, this agent has significant hepato- and cardiotoxicity and preclinical preliminary experiments indicate potential pneumotoxic effects. Accordingly, we sought to evaluate the acute effects of [Au(dppe)2]+ on pulmonary removal of two radioiodinated benzylguanidines [metaiodobenzylguanidine (MIBG) and 3-iodo-4-amino-benzylguanidine (AIBG)]. Pulmonary removal of MIBG or AIBG was measured by application of indicator dilution techniques in rabbit lungs, perfused with Kreb's bicarbonate (3% albumin; 50 ml/min). A bolus containing either [125I]MIBG or--AIBG and [99mTc]sulfur colloid was injected into the pulmonary artery and effluent was diverted to an in-line nuclear detection system. In initial experiments we characterized some pharmacokinetic aspects of the disposition of these amines. Removal of MIBG [R(MIBG)] and R(AIBG) were 59 +/- 3% (n = 14) and 24 +/- 2% (n = 7), respectively. Addition of unlabeled norepinephrine, MIBG or AIBG (3-100 nmol) to the injection caused similar dose-dependent reductions in removal of either amine. Lowering the temperature (13 degrees C) or reducing the sodium concentration caused significant reductions in removal. After 15 min of perfusion with [Au(dppe)2]+ (50 micrograms/ml), perfusion pressure doubled and R(MIBG) and R(AIBG) were each decreased significantly. At 30 min, perfusion pressure returned to control values whereas there was still a 36 and 61% reduction in R(MIBG) and R(AIBG), respectively. These data confirm that removal of benzylguanidines involves a saturable, sodium- and temperature-dependent process similar to that responsible for the removal of norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania.
W L
WL
Weng
J S
JS
Lazo
C N
CN
Gillis
B R
BR
Pitt
D019797:3-Iodobenzylguanidine / Q000031:analogs & derivatives; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D007457:Iodine Radioisotopes; D007462:Iodobenzenes / Q000493:pharmacokinetics*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010477:Perfusion; D011817:Rabbits
D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; C049322:4-amino-3-iodobenzylguanidine; D019797:3-Iodobenzylguanidine; C050185:bis(1,2-bis(diphenylphosphino)ethane)gold(I); D009638:Norepinephrine