Pharmacokinetics, Biodistribution and Elimination of Recombinant Human Homoserine Thymosin α1 in Rats and Mice
MA Jian-xiu1, LEI Ze-lin2, ZHONG Jian-bing1, MA Yan-qing1, JIN Long1
1. School of Medicine, Northwest University for Nationalities, Gansu Province Lanzhou 730030, China; 2. Donggang Branch of First Hospital of Lanzhou University, Gansu Province Lanzhou 730020, China
Abstract：Objective: To study the pharmacokinetic, distribution and elimination properties of rhTα1 after intravenous (i.v.) and subcutaneous (s.c.) injection in mice and rats. Methods: Competition ELISA was used for testing drug concentration in serum, urine, bile and tissue after administration of rhTα1 in mice (0.16, 0.5, 2.5 mg/kg) and rats (0.32, 1, 5 mg/kg). Pharmacokinetic parameters were calculated by WinNolin software. Results: Absorption of rhTαl is rapid in both mice and rats after s.c. administration. The pharmacokinetics in mice are characterized by linear, T1/2 showed a prolongation with increasing dose, 1.10, 1.35, and 1.50 h corresponding to 0.32, 1 and 5 mg/kg respectively, but in rats T1/2 showed no difference among doses. AUC0-∞ showed a clear increase with increasing doses in mice (904.18, 2998.83, and 19001.82 h*ng/mL) and in rats (1327.56±237.00, 2924.53±685.14, and 35286.26±5999.58 h*ng/mL). After i.v. administration of 1 mg/kg rhTα1 in mice, the drug is seen distributed in most organs, the thymus/ serum exposure ratio was higher than others at the 1 and 2 h, the accumulative urinary excretion of primary drug was 32.97%±15.85% within 6 h. Conclusion: The results indicate that rapid absorption, extensive distribution and quick renal excretion were the basic kinetic characteristics of rhTαl after s.c. and i.v. administration.
. [J]. 中国生物医学工程学报(英文版）, 2017, 26(3): 114-128.
MA Jian-xiu, LEI Ze-lin, ZHONG Jian-bing, MA Yan-qing, JIN Long. Pharmacokinetics, Biodistribution and Elimination of Recombinant Human Homoserine Thymosin α1 in Rats and Mice. Chinese Journal of Biomedical Engineering, 2017, 26(3): 114-128.
[1] Goldstein AL, Guha A, Zatz MM, et al. Purification and biological activity of thymosin, a hormone of the thymus gland[J]. Proceedings of the National Academy of Sciences, 1972, 69(7): 1800-1803. [2] Tuthill C, Rios I, McBeath R. Thymosin alpha 1: past clinical experience and future promise[J]. Annals of the New York Academy of Sciences, 2010, 1194(1): 130-135. [3] Knutsen AP, Freeman JJ, Mueller, et al. Thymosin-alpha1 stimulates maturation of CD34+ stem cells into CD3+4+ cells in an in vitro thymic epithelia organ coculture model[J]. International Immunopharmacology, 1999, 21(1): 15-26. [4] Esipov RS, Gurevich AI, Stepanenko VN, et al. Recombinant thymosin alpha1[J]. Russian Journal of Bioorganic Chemistry, 2004, 30(5): 481-486. [5] Shi J, Zhang Y, Zhao Y, et al. Expression of thymosin alpha 1 gene in E.coli and its purification and characterization[J]. Chinese Journal of Biochemistry and Molecular Biology, 2001. [6] Xu X, Vugmeyster Y. Challenges and opportunities in absorption, distribution, metabolism, and excretion studies of therapeutic biologics[J]. The AAPS Journal, 2012, 14(4): 781-791. [7] Naylor PH, Naylor CW, Sasaki D, et al. Utilization of HPLC-ELISA to assess serum levels of thymosin α1 following subcutaneous administration to human subjects[J]. Journal of Liquid Chromatography & Related Technologies, 1994, 17(16): 3541-3551. [8] Badamchian M. Biodistribution of synthetic thymosin α1 in the serum, urine and major organs of mice[J]. International Journal of Immunopharmacology, 1997, 19(2): 59-66. [9] Wang B, He F, Lin Y, et al. Effect of recombinant human thymosin-alpha1, an immuno-modulating peptide with 28amino acids, on the activity of cytochrome P450s[J]. Drug Metabdism Letters, 2007, 1(3): 199-204. [10] Weller FE, Mutchnick MG, Keren DF, et al. MicroELISA method for measurement of human serum thymosin α1[J]. Journal of Immunological Methods, 1985, 80(1): 45-53. [11] Damen CW, Schellens JH, Beijnen JH. Bioanalytical methods for the quantification of therapeutic monoclonal antibodies and their application in clinical pharmacokinetic studies[J]. Human Antibodies, 2009, 18(3): 47-73. [12] Colbert A, Umbleromero A, Prokop S, et al. Characterization of a quantitative method to measure free proprotein convertase subtilisin/kexin type 9 in human serum[J]. MABS, 2014, 6(4): 1103-1113. [13] Zollner S, Schuermann D, Raquet E, et al. Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP)[J]. Journal of Thrombosis & Haemostasis, 2014, 12(2): 220-228. [14] Jawa V, Cousens LP, Awwad M, et al. T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation[J]. Clinical Immunology, 2013, 149(3): 534-555. [15] Rost KL, Wierich W, Masayuki F, et al. Pharmacokinetics of thymosin alpha1 after subcutaneous injection of three different formulations in healthy volunteers[J]. International Journal of Clinical Pharmacdogy & Therapeutics, 1999, 37(1): 51-57. [16] Ma Jianxiu, Gao MT, Li Wengvang, et al. Pharmacokinetic study of synthetic thymosinα1 in mice and rats with intravenous and subcutaneous administration[J]. China Pharmacy, 2011.
