Investigations into the route of uptake and pharmacokinetics of intraperitoneally-administered monoclonal antibodies: I. Transdiaphragmatic blockade of the terminal lymphatics in the rat.
Recent studies on the intraperitoneal administration of radiolabeled monoclonal antibodies indicate that the diaphragm and, in particular, the lymphatics associated with the diaphragm are more involved in the transport of such high-molecular-mass moieties than was earlier suspected. The current study examines the role of the diaphragm in the i.p. transport of an IgG2a murine monoclonal antibody, 5G6.4, by observing the effect on the absorption of the antibody produced when the diaphragm has been scarred. Normal, sham-operated, and diaphragmatically scarred (abrasions made with 600-grade sandpaper) female Sprague Dawley rats (150-250 g) were administered intraperitoneal injections of 125labeled 5G6.4 in a volume of 2.0 cm3. Approximately 5 micrograms antibody protein was administered in the individual 19-microCi injections per rat. Scarring was effective in partially blocking the amount of labeled antibody that crossed the diaphragm. Mean diaphragm levels (% injected dose/g) of 125I-labeled 5G6.4 from the scarred group were 16.8% lower than values from the sham-operated rats and 37.2% lower than those from the control rats. The blockade was effective in slowing the appearance of the labeled antibody in the systemic circulation. The half-time to absorption was significantly prolonged in the scarred group; mean t1/2 absorption values of 2.5 h for the control group, 5.3 h for the sham-operated group, and 9.6 h for the diaphragmatically blocked group were recorded. Scarring the diaphragm reduced the mean maximum blood concentration by 27.6% over the control group and 23.9% over the sham-operated group. The mean time to maximum blood concentration was lengthened by 93..0% over the control group and 35.3% over the sham-operated group due as a result of scarification. Presumably this impedence to absorption would increase the time that the radiolabeled antibody bathed the peritoneal space. The scarred group also had the largest "system mean residence time" (162.5 h) compared to the sham-operated (147.9 h) and control (118.7 h) groups. These values further verify the effect of surgery on the kinetics of the i.p. administered radiolabeled monoclonals. This work demonstrates that scarifying the diaphragm does alter the kinetics of the i.p. administered monoclonal antibodies and supports the concept that transdiaphragmatic lymphatic absorption is an important route of antibody clearance from the peritoneal cavity.
Barrett
J S
JS
University of Michigan Medical Center, Division of Nuclear Medicine, Ann Arbor 48109-0028.
Wahl
R L
RL
Wagner
J G
JG
Brown
R
R
Fisher
S J
SJ
D000042:Absorption; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism*; D003964:Diaphragm / Q000378:metabolism*; D005260:Female; D007074:Immunoglobulin G / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007457:Iodine Radioisotopes; D008208:Lymphatic System / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes