Effect of intraperitoneal injection volume and antibody protein dose on the pharmacokinetics of intraperitoneally administered IgG2a kappa murine monoclonal antibody in the rat.
The i.p. route of antibody administration offers a regional delivery advantage to the peritoneal cavity. In an effort to optimize this method of delivery, the volume of i.p. injection and total protein dose were examined for their effect on the absorption and disposition of an IgG2a kappa murine monoclonal antibody. 5G6.4, administered i.p. Normal rats (Sprague-Dawley) were given one of two protein doses (1-2 or 100 micrograms) of 125I-5G6.4 in a 2.0-ml i.p. injection volume. In both cases the same radiation dose (approximately 20 mu Ci/rat) was administered since only the tracer level (1-2 micrograms) was labeled. Hence, the 100-micrograms dose consisted of approximately 2 micrograms of labeled antibody with 98 micrograms of unlabeled antibody. In a separate experiment, two i.p. injection volumes (2.0 or 20.0 ml) of 125I-5G6.4 (approximately 20 mu Ci/rat) were administered to normal Sprague-Dawley rats. Pharmacokinetic modeling of the whole blood radioactivity levels was undertaken for both groups. The liver, kidney, muscle, lung, diaphragm, and anterior mediastinal lymph nodes were excised upon sacrifice and tissue levels at sacrifice were recorded. The volume of i.p. injection is shown to be a significant factor with respect to i.p. transport. Maximum concentration in the blood, Cmax, was reduced (P less than 0.1) and time of maximum concentration, tCmax was prolonged (P less than 0.05) from 8.4 h (in the 2-ml group) to 14.5 h (in the 20-ml group). Both contribute to a modest reduction in AUC(0----infinity) (P less than 0.15) in which AUC is the area under the concentration-time curve. The increase in blood clearance, Clb, at the higher injection volume (0.287 ml/h for the 20-ml volume and 0.194 ml/h for the 2-ml volume) is presumably due to increased diuresis resulting from autoregulation of fluid removal via lymphatic drainage. Volume of distribution, Vd, is increased since Vd and Clb are functionally proportionate and elimination is assumed constant. Tissue levels at sacrifice, except for the thyroid and anterior mediastinal lymph nodes, were the same. Mean thyroid levels were reduced in the 20-ml group (P less than 0.05) by 22.5%, likely as a result of increased diuresis. Increased nodal uptake (P less than 0.01) can be attributed to the dilution effect of the bolus injection. The rate of mass transfer is greater for the 2-ml group up to 4 h postinjection. Subsequently, the mass transfer rate is greater for the 20-ml group.(ABSTRACT TRUNCATED AT 400 WORDS)
Barrett
J S
JS
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109.
Wagner
J G
JG
Fisher
S J
SJ
Wahl
R L
RL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000912:Antibodies, Neoplasm / Q000493:pharmacokinetics; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007145:Immunoglobulin kappa-Chains; D007274:Injections, Intraperitoneal; D051381:Rats; D013961:Thyroid Gland / Q000378:metabolism; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains