Pharmacokinetics and distribution of clioquinol in golden hamsters.
Clioquinol (5-chloro-7-iodo-8-quinolinol) is a zinc and copper chelator that can dissolve amyloid deposits and may be beneficial in Alzheimer's disease. Prion diseases are also degenerative CNS disorders characterised by amyloid deposits. The pharmacokinetics and tissue distribution of drugs active against prions may clarify their targets of action. We describe the pharmacokinetics of clioquinol in hamster plasma, spleen and brain after single and repeated oral or intraperitoneal administration (50 mg kg(-1)), as well as after administration with the diet. A single intraperitoneal administration led to peak plasma clioquinol concentrations after 15 min (Tmax), followed by a decay with an apparent half-life of 2.20 +/- 1.1 h. After oral administration, Tmax was reached after 30 min and was followed by a similar process of decay; the AUC(0-last) was 16% that recorded after intraperitoneal administration. The Cmax and AUC values in spleen after a single administration were about 65% (i.p.) and 25% (p.o.) those observed in blood; those in liver were 35% (p.o.) those observed in blood and those in brain were 20% (i.p.) and 10% (p.o.) those observed in plasma. After repeated oral doses, the plasma, brain and spleen concentrations were similar to those observed at the same times after a single dose. One hour after intraperitoneal dosing, clioquinol was also found in the ventricular CSF. Clioquinol was also given with the diet; its morning and afternoon concentrations were similar, and matched those after oral administration. No toxicity was found after chronic administration. Our results indicate that clioquinol, after oral administration with the diet, reaches concentrations in brain and peripheral tissues (particularly spleen) that can be considered effective in preventing prion accumulation, but are at least ten times lower than those likely to cause toxicity.
Bondiolotti
Gianpietro
G
Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.
Sala
Mariaelvina
M
Pollera
Claudia
C
Gervasoni
Marco
M
Puricelli
Maria
M
Ponti
Wilma
W
Bareggi
Silvio R
SR
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002614:Chelating Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007464:Clioquinol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006224:Cricetinae; D005260:Female; D018565:Food-Drug Interactions; D014018:Tissue Distribution
D002614:Chelating Agents; D007464:Clioquinol