SHORT-TERM ORAL 3-HYDROXYPYRIDIN-4-ONE DOSING INCREASES ALUMINUM EXCRETION AND PARTIALLY REVERSES ALUMINUM-INDUCED TOXICITY IN THE RABBIT INDEPENDENT OF CHELATOR LIPOPHILICITY
Ra. Yokel et al., SHORT-TERM ORAL 3-HYDROXYPYRIDIN-4-ONE DOSING INCREASES ALUMINUM EXCRETION AND PARTIALLY REVERSES ALUMINUM-INDUCED TOXICITY IN THE RABBIT INDEPENDENT OF CHELATOR LIPOPHILICITY, Drug metabolism and disposition, 25(2), 1997, pp. 182-190
The objectives of the present study were to determine the efficacy and
toxicity of repeated oral administration of 3-hydroxypyridin-4-one (H
P) chelators in a rabbit model of aluminum (Al) accumulation and toxic
ity, and the influence of chelator lipophilicity on these effects. Eff
icacy was assessed as chelator-induced Al mobilization and excretion a
nd reversal of Al accumulation and Al-induced toxicity. Chelator-induc
ed toxicity was assessed by multiple measures, Six HPs were given oral
ly 12 times over 1 month to Al-loaded rabbits, which had significant e
levation of Al in most tissues and evidence of Al-induced nephrotoxici
ty, osteomalacia, and anemia, Intravenous desferrioxamine (DFO), the c
urrent chelator of choice for the treatment of Al-overload and toxicit
y, was included as a positive control. All six HPs and DFO demonstrate
d efficacy evidenced by significantly greater urinary and biliary Al e
limination after the twelfth dose than seen in saline-treated controls
, All of the HPs were more effective than DFO, Chelator-induced urinar
y Al excretion accounted for 58-98% of total (urinary plus biliary) Al
excretion. Chelator-facilitated Al excretion was nearly complete with
in 12 hr, demonstrating a fairly short duration of action in rabbits w
ith intact renal function. HP treatments did not consistently affect t
issue concentrations of Al or other metals. However, there was a trend
toward chelator-induced reduction of Al-induced nephrotoxicity. The i
nfluence of HP lipophilicity was limited to a positive correlation bet
ween HP Al lipophilicity and biliary Al output and a negative correlat
ion between HP and HP Al lipophilicity and reduction of Kupffer cell A
l. Little toxicity was evident after repeated oral HP dosing. Adrenal
weight increased after treatment with several HPs, There was a decreas
e in testes weight after several HPs, which is consistent with an anti
proliferative effect, More frequent dosing and/or a longer duration of
HP treatment might produce greater reversal of the Al-induced toxicit
y and perhaps reveal more adverse effects than seen in this study. The
re was a lack of profound toxicity during this short-term study, The 1
,2-dimethyl (CP20) and 1,2-diethyl (CP94) HPs, which have been the mos
t extensively studied HPs, were the least effective of the HPs examine
d, These results encourage the further investigation of other HPs as o
ral alternatives to DFO for the treatment of Al accumulation and toxic
ity.