Acta Pharmacologica Sinica 2008 November; 29 (11): 1383-1390; doi: 10.1111/j.1745-7254.2008.00885.x

Acta Pharmacologica Sinica 2008 November; 29 (11): 1383-1390; doi: 10.1111/j.1745-7254.2008.00885.x

Original Article

Pharmacokinetic and toxicity study of intravitreal erythropoietin in rabbits¹

Jing-fa ZHANG², Ya-lan WU², Jing-ying XU², Wen YE³, Yu ZHANG³, Huan WENG³, Wo-dong SHI⁴, Guo-xu XU⁵, Luo LU², Wei DAI², Stephen H SINCLAIR⁸, Wei-ye LI^2,6,8,9,10, Guo-tong XU^2,7,9,10

²Laboratory of Clinical Visual Sciences, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai 200025, China; ³Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China; ⁴Department of Ophthalmology, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai 200011, China; ⁵Department of Ophthalmology, Second Affiliated Hospital of Suzhou University, Suzhou 215004, China;⁶Department of Ophthalmology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China; ⁷Laboraotry of Clinical Visual Sciences, Tongji Eye Institute, and Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200092, China; ⁸Department of Ophthalmology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

Aim: To study the pharmacokinetics and toxicity of intravitreal erythropoietin (EPO) for potential clinical use.

Methods: For toxicity study, 4 groups (60 rabbits) with intravitreal injection (IVit) of EPO were studied (10 U, 100 U, or 1 000 U) per eye for single injection and 0.6 U/eye (the designed therapeutic level in rabbits) for monthly injections (6×). Eye examination, flash electroretinogram (ERG), and fluorescein angiography (FA) were carried out before and after injection. The rabbits were killed for histological study at different intervals. For the pharmacokinetic study, after IVit of 5 U EPO into left eyes, 44 rabbits were killed at different intervals, and the EPO levels in vitreous, aqueous, retina and serum were analyzed by enzyme-linked immunosorbent assay.

Results: At all of the time points examined, the eyes were within normal limits. No significant ERG or FA change was observed. The histology of retina remained unchanged. The pharmacokinetic profile of EPO in ocular compartments was summarized as follows. The half-life times of EPO in vitreous, aqueous and serum were 2.84, 3.24 and 2.12 d, respectively; and C_max were 4615.75, 294.31 and 1.60 U/L, respectively. EPO concentrations in the retina of the injected eye peaked at 1.36 U/g protein at 6 h following injection, with the half-life observed to be 3.42 d.

Conclusion: IVit of EPO in a wide range is well tolerated and safe for rabbit eyes. At doses up to 10-fold higher than therapeutic levels, EPO has a pharmacokinetic profile with faster clearance, which is favorable for episodic IVit.

Keywords: ocular toxicity; pharmacokinetics; intravitreal injection; erythropoietin

¹This work was supported by the following research grants: China National Program on Key Basic Research Project (973), No 2004CB- 720300; Unrestricted Research Fund from the Clear Vision Foundation, Philadelphia USA; Sciences and Technology Commission of Shanghai Municipality International Cooperative Research Grant (No 054107058 and 08410- 701200).

⁹Wei-ye LI and Guo-tong Xu contributed equally to this study.
¹⁰Correspondence to Dr Guo-tong XU and Dr Wei-ye LI.
Phn 86-21-6385-2722.
Fax 86-21-6385-2655.
E-mail gtxu@sibs.ac.cn (Dr Guo-tong XU)
Phn 86-1-610-892-1708.
Fax 86-1-610-892-8766.
E-mail weiye.li@drexelmed.edu (Dr Wei-ye LI)
Received 2008-05-08 Accepted 2008-08-27

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