| Objective: To determine electrophysiological examination and platinum concentrations and area under the concentration versus time curve(AUC) of the vitreous humor and plasma after periocular or intravenous administration of carboplatin in rabbits,then study the safty and relation between dosage and AUC of vitreous.Methods: Sixteen rabbits were included in an in vivo experiment. Each animal received a single dose of either 5 mg of carboplatin by periocular injection(POI5 group: n=4) or 10 mg by periocular injection(POI10 group: n=4), or 20 mg by periocular injection(POI20 group: n=4), or 18.7 mg/kg by intravenous injection(IV group: n=4),respectively, into the right eyes.Vitreous humor from the right eyes and plasma samples were collected post dose at 1, 3, 6, 24, 48, 168, and 336 hours, respectively. Flameless atomic absorption spectroscopy was employed to analyze total platinum concentration in vitreous humor and plasma.Flash electroretinograms(FERG) and flash visual evoked potential(FVEP) were recorded before the carboplatin injection and after the last collection. At the end of experiments, all rabbit eyes were obtained for histopathologic examination. AUC was calculated using the trapezoidal rule. One-Way ANOVA, Paired-sample T test and Pearson’s test were used to analysis.Results: 1.The Cmax in vitreous humor samples reached at 3h after POI and IV carboplatin。The vitreous Cmax of group POI20,POI10 and POI5 were 1.50±0.02 mg/L, 0.73±0.02 mg/L and 0.39±0.03 mg/L respectively,which were significantly higher than that of the group IV(0.35±0.05 mg/L)(P<0.05). The AUC0-336 h of the group POI20, POI10, and POI5 were 38.06±2.68 mg·h/L, 16.97±1.50 mg·h/L and 8.69±1.20 mg·h/L(P<0.05).But there was no statistical difference(P > 0.05) between the AUC0-336 h of the group POI10 and IV(15.56±1.72 mg·h/L). The AUC0-∞ of the group POI5,POI10 and POI20 were 9.43±1.52 mg·h/L, 18.35±2.65 mg·h/L and 38.32±2.69 mg·h/L(P<0.05).But the AUC0-∞ of group IV(16.45±1.99 mg·h/L) and POI10(18.35±2.65 mg·h/L) were not statistically significant(P>0.05). 2.The Tmax of both the group IV and POI in the plasma were 1h after administration.And the Cmax of all of the groups POI were significantly lower(P<0.05) than that of the group IV(3.88±0.11 mg/L). The AUC0-336h(41.90±1.51 mg·h/L)and AUC0-∞(44.19±1.32 mg·h/L)of the group IV were significantly higher(P<0.05) compared to those of the other POI groups.. 3.The ratio of the AUC0-∞ in the vitreous humor and plasma of the group IV was 0.37,which was statistically lower(P<0.05) than those of the group POI5(1.30), POI10(1.50) and POI20(1.38). 4.The Pearson product-moment correlation coefficient was calculated, r=0.990,P<0.001.There might be positive correlation between AUC of platinum in the rabbit vitreous humor and dosages of periocular delivery. 5.The FERG showed that there was no statistically significant difference(P>0.05) before and after administration in terms of the dark-adapted a-wave,b-wave and ops wave amplitudes.The FVEP indicated that the latentperiod of N1-wave,P1-wave and P2 wave had no statistical difference(P > 0.05) before and after periocular or intravenous delivery.There were no histopathologic retinal changes.Conclusion: These findings proves that periocular carboplatin delivery enables the achievement of relatively high concentrations and AUC of platinum in the rabbit vitreous humor and low systemic exposure.The AUC of platinum in the rabbit vitreous humor is direct proportion to dosages of periocular delivery within 20 mg and did not show toxity in two weeks. |
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