Comparison of the pharmacokinetics of subcutaneous and intravenous administration of a phosphorothioate oligodeoxynucleotide in cynomolgus monkeys.
Antisense Nucleic Acid Drug Dev
; 10(6): 435-41, 2000 Dec.
Article
en En
| MEDLINE
| ID: mdl-11198927
ABSTRACT
The pharmacokinetics of subcutaneous (s.c.) administration of a phosphorothioate oligodeoxynucleotide (PS-ODN) was evaluated in cynomolgus monkeys. In a single dose study, monkeys were injected s.c. or intravenously (i.v.) with doses of either 1 or 5 mg/kg ISIS 2302. The bioavailability of s.c. injection ranged from 26% to 55% and appeared to be dependent on the concentration of the dosing solution rather than the dose. The bioavailability of a subcutaneously administered 5 mg/kg dose of ISIS 2302 was 55% using a 50 mg/ml dosing solution and only 26% using a 10 mg/ml dosing solution. Slow absorption from the s.c. injection site significantly blunted the maximal concentration (Cmax) compared with i.v. administration. The time to peak plasma concentration (Tmax) increased slightly with increasing dose, from 0.5 to 1 hour for the 1 mg/kg dose to 1 to 2.5 hours for the 5 mg/kg dose. Plasma half-lives were prolonged after s.c. administration, indicating more dependence on absorption than elimination. The half-lives after s.c. administration averaged 3 hours, whereas after i.v. administration, the half-lives were <1 hour. Metabolism of the ISIS 2302 after s.c. injection was consistent with exonucleolytic cleavage, as previously observed after i.v. administration. In summary, s.c. administration of PS-ODN resulted in prolonged and extensive absorption of the ODN.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tionucleótidos
/
Oligodesoxirribonucleótidos Antisentido
Límite:
Animals
Idioma:
En
Revista:
Antisense Nucleic Acid Drug Dev
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
FARMACOLOGIA
Año:
2000
Tipo del documento:
Article
País de afiliación:
Estados Unidos