Lymphatic transport and catabolism of therapeutic proteins after subcutaneous administration to rats and dogs.
نویسندگان
چکیده
The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ∼70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2- to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.
منابع مشابه
Lymphatic Transport and Catabolism of Therapeutic Proteins Following Subcutaneous Administration to Rats and Dogs
متن کامل
Dmd059238 1881..1889
Subcutaneous administration of biotherapeutics offers several potential advantages compared with intravenous administration. Many biotherapeutics, both marketed or in development, are administered via the subcutaneous route. This minireview provides an overview of the presystemic absorption processes following subcutaneous administration, the resulting pharmacokinetics after subcutaneous admini...
متن کاملDiabetic Encephalopathy Affects Mitochondria and Axonal Transport Proteins
Introduction: Diabetic encephalopathy is described as any cognitive and memory impairments and associated with hippocampal degenerative changes, include neurodegenerative process and decreased number of living cell. Mitochondrial Diabetes (MD) appears fallowing activation of mutant mitochondrial DNA and is combination of diabetes and cognitive deficit. In this research we showed the correlation...
متن کاملTHE EFFECT OF EIGHT WEEKS OF HIGH INTENSITY INTERVAL TRAINING ON CREB AND CRTC2 PROTEINS LEVELS IN SUBCUTANEOUS ADIPOSE TISSUE OF OBESE RATS WITH TYPE 2 DIABETES
Background: Obesity and type 2 diabetes can impair the function of cells, including CREB and CRTC2 proteins, which are important for regulating adipose tissue metabolism. Therefore, the purpose of the present study was to investigate the effect of eight weeks of high intensity interval training (HIIT) on CREB and CRTC2 proteins levels in subcutaneous adipose tissue of obese rats with type 2 dia...
متن کاملLymphatic transport of Methylnortestosterone undecanoate (MU) and the bioavailability of methylnortestosterone are highly sensitive to the mass of coadministered lipid after oral administration of MU.
The contribution of lymphatic transport to the oral bioavailability of methylnortestosterone (M) after oral administration of the lipophilic prodrug methylnortestosterone undecanoate (MU) has been evaluated, and the sensitivity of lymphatic MU transport to lymphatic lipid transport has been investigated. M and MU were administered intravenously and orally to greyhound dogs to determine absolute...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 40 5 شماره
صفحات -
تاریخ انتشار 2012