Pharmacokinetics and distribution of sodium 3,4-diaminonaphthalene-1-sulfonate, a Congo Red derivative active in inhibiting PrP(res) replication.
Sodium 3,4-diaminonaphthalene-1-sulfonate (CRA) is a compound, synthesised by our group from Congo Red (CR), that is active in preventing the pathological conversion of normal prion protein (PrP). As the precise mechanisms controlling the ways in which prions are distributed and infect the brain and other organs are not fully understood, studying the pharmacokinetics of drugs that are active against prions may clarify their targets and their means of inhibiting prion infection. This paper describes the pharmacokinetics of CRA in plasma, spleen and brain after single or repeated intraperitoneal or subcutaneous administration, as determined by means of specific and sensitive fluorimetric HPLC. A single intraperitoneal administration led to peak plasma CRA concentrations after 15 min, followed by biphasic decay with an apparent half-life of 4.3 h. After subcutaneous administration, T(max) was reached after 30 min, and was followed by a similar process of decay: Cmax and the AUC0-last were 25% those recorded after intraperitoneal administration. The mean peak concentrations and AUCs of CRA after a single intraperitoneal or subcutaneous administration in peripheral tissue (spleen) were similar to those observed in blood, whereas brain concentrations were about 2% those in plasma. After repeated intraperitoneal or subcutaneous doses, the Cmax values in plasma, brain and spleen were similar to those observed at the same times after a single dose. After repeated intraperitoneal doses, CRA was also found in the ventricular cerebrospinal fluid at concentrations of 1.8 +/- 0.2 microg(-1) mL, which is similar to, or slightly higher than, those found in brain. Brain concentrations may be sufficient to explain the activity of CRA on PrP reproduction in the CNS. However, peripheral involvement cannot be excluded because the effects of CRA are more pronounced after intraperitoneal than after intracerebral infection.
Gervasoni
M
M
Department of Pharmacology, Chemotherapy and Medical Toicology, School of Medicine, University of Milan, Italy.
Pirola
R
R
Pollera
C
C
Villa
S
S
Cignarella
G
G
Mantegazza
P
P
Poli
G
G
Bareggi
S R
SR
D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry; D003224:Congo Red / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D006224:Cricetinae; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D018621:PrPC Proteins / Q000187:drug effects / Q000472:pathogenicity; D013154:Spleen / Q000737:chemistry / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects* / Q000502:physiology
D018621:PrPC Proteins; C465798:sodium 3,4-diaminonaphthalene-1-sulfonate; D003224:Congo Red