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Titolo:
PHARMACOKINETICS AND BIODISTRIBUTION OF A NUCLEOTIDE-BASED THROMBIN INHIBITOR IN RATS
Autore:
REYDERMAN L; STAVCHANSKY S;
Indirizzi:
UNIV TEXAS,COLL PHARM,DIV PHARMACEUT,PHR 4-214C AUSTIN TX 78712 UNIV TEXAS,COLL PHARM,DIV PHARMACEUT AUSTIN TX 78712
Titolo Testata:
Pharmaceutical research
fascicolo: 6, volume: 15, anno: 1998,
pagine: 904 - 910
SICI:
0724-8741(1998)15:6<904:PABOAN>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
H-3 LABELED OLIGONUCLEOTIDES; ANTISENSE OLIGONUCLEOTIDES; PHOSPHOROTHIOATE OLIGONUCLEOTIDE; OLIGODEOXYNUCLEOTIDE INHIBITOR; STABILITY; PLASMA; METABOLISM; MICE;
Keywords:
GS522; OLIGODEOXYNUCLEOTIDE; PHARMACOKINETICS; TRITIATED; BIODISTRIBUTION; RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
18
Recensione:
Indirizzi per estratti:
Citazione:
L. Reyderman e S. Stavchansky, "PHARMACOKINETICS AND BIODISTRIBUTION OF A NUCLEOTIDE-BASED THROMBIN INHIBITOR IN RATS", Pharmaceutical research, 15(6), 1998, pp. 904-910

Abstract

Purpose, To characterize the pharmacokinetic and tissue distribution profiles of a nucleotide-based thrombin inhibitor (GS522, phosphodiester oligonucleotide, GGTTGGTGTGGTTGG) following intravenous administration to rats. Methods. Pharmacokinetic study: 10 mg/kg, 20 mg/kg, 30 mg/kg (6 animals/dose) were administered to rats by rapid injection intothe femoral vein. Blood samples were collected over a 45 minute period. Plasma concentrations of GS522 were determined using capillary gel electrophoresis with laser-induced fluorescence detection. Biodistribution Study: 10mg/kg (400 mu l, 31.46 mu Ci/ml) of H-3-GS522 was administered to rats by rapid injection into the femoral vein. The animals were sacrificed by decapitation at 1, 5, 10, 30, 60, 360 minutes post-dose (3 rats/point), Brain, blood, duodenum, eyes, heart, kidney, liver, lungs, muscle, pancreas, skin, spleen and vein samples were collected, processed and quantitated using liquid scintillation counting. Results. The pharmacokinetic profile declines in multiexponential manner, exhibiting extremely fast distribution and elimination (t(1/2) = 7.6-9.0 min, Cl = 22.0-28.0 ml/min, V = 83.9-132.4 ml/kg). GS522 follows linear pharmacokinetics, with the area under the curve being proportional to the dose (Rsq = 0.9744). Highest radioactivity levels were detected in kidney, liver and blood (39.7, 15.7 and 15.3% dose/ respective organ). Less than 1% of the dose was detected in the heart, spleen and lungs, and >0.3% of the dose was found in the brain and eyes. The oligonucleotide associated radioactivity was uniformly distributed betweenthe brain regions (left and right lobe and cerebellum). Six hours following the dose administration a statistically significant increase (p< 0.05)in radioactivity levels was observed in the brain, eyes, skin,liver, pancreas and vein. Conclusions. The pharmacokinetic and biodistribution profiles of GS522 following intravenous administration to rats at three doses were characterized. The oligonucleotide associated radioactivity was widely distributed in tissues. The amount of radioactivity sharply decreased with time in most tissues. Kidney, liver and muscle were the main sites of accumulation. The oligonucleotide associated radioactivity did not cross the blood brain barrier to an appreciable extent. In addition, a statistically significant increase (p < 0.05) in the radioactivity levels observed in select tissues suggested a re-uptake mechanism for intact oligonucleotide or its degradation products.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/09/20 alle ore 20:16:46