Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 363 Hochstetter Hall, Buffalo, New York 14260, USA.
Pharm Res. 2012 Feb;29(2):490-9. doi: 10.1007/s11095-011-0578-3. Epub 2011 Sep 2.
To determine the effect of dose, the anatomical site of injection, and the injection volume on subcutaneous absorption of rituximab in rats and to explore absorption mechanisms using pharmacokinetic modeling.
Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back, abdomen, and foot of rats. Several pharmacokinetic models were developed that included linear and saturable absorption, and degradation and/or protective binding at the injection site.
Rituximab exhibited linear kinetics following intravenous administration; however, bioavailability following subcutaneous injection was inversely related to the dose level. For the 1 mg/kg dose, bioavailability was approximately 70% at all tested injection sites, with faster absorption from the foot (T(max) = 12 h for foot vs. 4.6 days for back). Bioavailability for the 10 mg/kg dose was 44 and 31% for the abdomen and back sites and 18% for 40 mg/kg injected at the back. A pharmacokinetic model that included binding as part of the absorption mechanism successfully captured the nonlinearities in rituximab absorption.
The anatomical site of subcutaneous injection influences the rate of absorption and bioavailability of rituximab in rats. Saturable binding may be a major determinant of the nonlinear absorptive transport of monoclonal antibodies.
确定剂量、注射部位和注射体积对大鼠皮下注射利妥昔单抗吸收的影响，并通过药代动力学模型探索吸收机制。
在大鼠背部、腹部和足部进行静脉和皮下给药后，测定利妥昔单抗的血清浓度。建立了几种药代动力学模型，包括线性和饱和吸收，以及在注射部位的降解和/或保护结合。
静脉给药后利妥昔单抗呈线性动力学；然而，皮下注射后的生物利用度与剂量水平呈反比。对于 1mg/kg 的剂量，在所有测试的注射部位的生物利用度约为 70%，足部吸收更快（T(max)=12 小时足部 vs. 背部 4.6 天）。对于 10mg/kg 剂量，腹部和背部的生物利用度分别为 44%和 31%，背部注射 40mg/kg 的生物利用度为 18%。一种药代动力学模型将结合作为吸收机制的一部分，成功地捕获了利妥昔单抗吸收的非线性。
皮下注射的解剖部位影响大鼠利妥昔单抗的吸收速度和生物利用度。饱和结合可能是单克隆抗体吸收转运的主要决定因素。
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