Pharmacokinetics of human activated protein C. 2nd communication: tissue distribution study of a lyophilized purified human activated protein C after single or repeated intravenous administration in male mice and placental transfer and milk passage study after intravenous administration in pregnant and lactating mice.
Tissue distribution studies of human activated protein C (CAS 42617-41-4, APC) were performed in mice after single or repeated administration, and placental transfer and milk passage study were investigated. At 15 min after a single intravenous administration of 125I-APC, radioactivity was mainly distributed to the blood and blood rich organ, such as liver, and then rapidly eliminated. The radioactivity distributed to tissues was almost negligible at 24 h after administration except for the thyroid. The qualitative study of the distribution of radioactivity to tissues by whole body autoradiography demonstrated the correspondence to the result of the quantitative assay of distribution of radioactivity after single administration of 125I-APC. The influence of repeated administration of APC on its pharmacokinetic disposition was studied by administering 125I-APC once a day to mice for 14 days. Though plasma radioactivity at 15 min in mice during repeated administration of 125I-APC was almost similar to that at 15 min after a single administration, the radioactivity at 24 h after administration was 2 times higher than that after a single administration. The profile of plasma radioactivity during and after repeated administration corresponded to the simulation curve which was described with the pharmacokinetic parameters obtained previously after the single administration. Distribution profile after repeated administration at 15 min after the 4th, 7th, 10th and 14th administration was almost similar to that at 15 min after a single administration except for the thyroid and spleen. In the thyroid, the radioactivity was 500 times higher than that after a single administration, and HPLC analysis demonstrated that the radioactivity was attributed to thyroglobulin. As to the spleen, the radioactivity was about 52% of that after a single administration. During the repeated administration, the spleen became larger than that after a single administration and the final weight was 2 times heavier than that of the non-treated animal. The decrease in radioactivity of the spleen during repeated administration was attributed to the hypertrophy of the organ. Placental transfer of 125I-APC was studied with pregnant mice quantitatively and qualitatively. Radioactivity distributed in fetuses was low at every point examined, and the result corresponded to the autoradiography. During lactation, radioactivity transferred to milk and milk to plasma ratio reached 5.7 after intravenous administration of 125I-APC. HPLC analysis of the milk radioactivity demonstrated that most of the radioactivity was present in the macromolecules produced by the lactating mother.
Ishii
S
S
Department of Drug Metabolism and Pharmacokinetics Research, Hamura Institute for Clinical Chemistry, Teijin Bio-Laboratories Inc., Tokyo, Japan.
Mochizuki
T
T
Nagao
T
T
Kudo
S
S
Fujita
A
A
Taniguchi
K
K
Kondo
S
S
Kiyoki
M
M
D000818:Animals; D001345:Autoradiography; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005612:Freeze Drying; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008892:Milk / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011486:Protein C / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
D007457:Iodine Radioisotopes; D011486:Protein C