PHARMACOKINETICS OF HUMAN ACTIVATED PROTEIN-C .2. TISSUE DISTRIBUTION 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 (GAS 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 I-125-APC, radioactivity was mainly distributed to the blood and blood rich organ, such as lit er, and then rapidly eliminated. The radioactivity distributed to tissues was almost negligeble 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 tire result of the quantitative assay of distribution of radioactivity after single administration of I-125-APC. The influence of repeated administration of APC on its pharmacokinetic disposition was studied by administering I-125-APC once a day to mice for 14 days. Though plasma radioactivity at 15 min in mice during repeated administration of I-125-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 repented administration corresponded to the simulation curve which uas described with the pharmacokinetic parameters obtained previously after the single administration. Distribution profile after repented 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 tire 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 tr,as attributed to the hypertrophy of the organ. Placental transfer of I-125-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 I-125-APC. HPLC analysis of the milk radioactivity demonstrated that most of the radioactivity was present in the macromolecules produced by the lactating mother.