ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
artículos
Título:
Topotecan vitreous levels after periocular or intravenous delivery in rabbits: an alternative for retinoblastoma chemotherapy
Autor/es:
CARBOSO AM., BRAMUGLIA GF., CHANTADA GL., FANDIÑO AC., CHIAPPETTA DA., DE AVILA MTG., RUBIO MC., ABRAMSON DH
Revista:
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Referencias:
Año: 2007 vol. 48 p. 3761 - 3767
ISSN:
0146-0404
Resumen:
Purpose. To determine the extent and the mechanism by which topotecan, a candidate agent for the treatment of retinoblastoma, gains access to the vitreous when administered by periocular injection or intravenous infusion. Methods. Topotecan in vitro scleral permeability was evaluated in excised sclera using diffusion cells. In vivo experiments included albino rabbits receiving 1 mg of topotecan either injected periocularly (PO group, n=23) or as a 30 min intravenous infusion (IV group, n=14). Plasma and vitreal topotecan concentrations were analyzed during 10 hours postadministration. A population pharmacokinetic model was fit to the data. Additionally, periocular injections were performed postmortem to study the effect of removing the blood vasculature barrier. Results. Under simulated intraocular pressure conditions, the permeability coefficient of topotecan was 5.2 ± 0.9 × 10-7 cm/s. Potentially active lactone topotecan levels were detected in the vitreous in the PO and IV groups. Both administration schedules induced equivalent plasma exposures due to the complete absorption from the periocular depot. Similar vitreal concentrations were found in both the treated and the control eyes in the PO group. The transfer from the periocular compartment to the vitreous was negligible. The absence of drug levels in the control eye of the postmortem injected rabbits confirmed the systemic delivery of topotecan. Local toxicity was not observed. Conclusion. As a consequence of a favored passage across the blood retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Trasscleral entry in vivo was constrained by a rapid clearance from the administration site.in vitro scleral permeability was evaluated in excised sclera using diffusion cells. In vivo experiments included albino rabbits receiving 1 mg of topotecan either injected periocularly (PO group, n=23) or as a 30 min intravenous infusion (IV group, n=14). Plasma and vitreal topotecan concentrations were analyzed during 10 hours postadministration. A population pharmacokinetic model was fit to the data. Additionally, periocular injections were performed postmortem to study the effect of removing the blood vasculature barrier. Results. Under simulated intraocular pressure conditions, the permeability coefficient of topotecan was 5.2 ± 0.9 × 10-7 cm/s. Potentially active lactone topotecan levels were detected in the vitreous in the PO and IV groups. Both administration schedules induced equivalent plasma exposures due to the complete absorption from the periocular depot. Similar vitreal concentrations were found in both the treated and the control eyes in the PO group. The transfer from the periocular compartment to the vitreous was negligible. The absence of drug levels in the control eye of the postmortem injected rabbits confirmed the systemic delivery of topotecan. Local toxicity was not observed. Conclusion. As a consequence of a favored passage across the blood retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Trasscleral entry in vivo was constrained by a rapid clearance from the administration site.In vivo experiments included albino rabbits receiving 1 mg of topotecan either injected periocularly (PO group, n=23) or as a 30 min intravenous infusion (IV group, n=14). Plasma and vitreal topotecan concentrations were analyzed during 10 hours postadministration. A population pharmacokinetic model was fit to the data. Additionally, periocular injections were performed postmortem to study the effect of removing the blood vasculature barrier. Results. Under simulated intraocular pressure conditions, the permeability coefficient of topotecan was 5.2 ± 0.9 × 10-7 cm/s. Potentially active lactone topotecan levels were detected in the vitreous in the PO and IV groups. Both administration schedules induced equivalent plasma exposures due to the complete absorption from the periocular depot. Similar vitreal concentrations were found in both the treated and the control eyes in the PO group. The transfer from the periocular compartment to the vitreous was negligible. The absence of drug levels in the control eye of the postmortem injected rabbits confirmed the systemic delivery of topotecan. Local toxicity was not observed. Conclusion. As a consequence of a favored passage across the blood retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Trasscleral entry in vivo was constrained by a rapid clearance from the administration site.± 0.9 × 10-7 cm/s. Potentially active lactone topotecan levels were detected in the vitreous in the PO and IV groups. Both administration schedules induced equivalent plasma exposures due to the complete absorption from the periocular depot. Similar vitreal concentrations were found in both the treated and the control eyes in the PO group. The transfer from the periocular compartment to the vitreous was negligible. The absence of drug levels in the control eye of the postmortem injected rabbits confirmed the systemic delivery of topotecan. Local toxicity was not observed. Conclusion. As a consequence of a favored passage across the blood retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Trasscleral entry in vivo was constrained by a rapid clearance from the administration site.in vivo was constrained by a rapid clearance from the administration site.