title: Effect of molecular weight (Mw) of N-(2-hydroxypropyl)methacrylamide copolymers on body distribution and rate of excretion after subcutaneous, intraperitoneal, and intravenous administration to rats.
abstract: A copolymer of N-(2-hydroxypropyl) methacrylamide (HPMA) and N-methacryloyltyrosinamide was prepared and fractionated using Sepharose 4B/6B (1:1) chromatography to produce eight HPMA copolymer fractions of narrow polydispersity and mean molecular weight (Mw) ranging from 12 to 778 kD. These fractions were radioiodinated and injected intravenously, subcutaneously, and intraperitoneally into rats. Their bloodstream-concentration profiles were monitored and rates of excretion assessed. Following intravenous administration the circulating blood volume available to the copolymers was not molecular-weight-dependent. A molecular-weight threshold limiting glomerular filtration was identified at approximately 45 kD, and preparations greater than this threshold were lost from the bloodstream only slowly by extravasation. Molecular weight did not influence the movement of copolymers from the peritoneal compartment to the bloodstream after intraperitoneal injection. The transfer rates observed could be accounted for by bulk phase lymphatic drainage alone, no transcapillary routes being implicated. Following subcutaneous administration the largest HPMA copolymer fraction (Mw = 778 kD, diameter approximately 30 nm) showed increased retention at the site of the injection, approximately 20% of the dose remaining there after 21 days. This could result from physical restriction of movement or from internalization into local phagocytic cells. The smaller copolymer fractions moved readily into the bloodstream whence they were either lost in the urine or they gradually penetrated into other tissues and organs. Long-term (21 days) body distribution of copolymers following both intraperitoneal and subcutaneous administration showed size-dependent accumulation in organs of the reticuloendothelial system.
authors: Department of Biological Sciences, University of Keele, United Kingdom.
authors: L W
authors: LW
authors: Seymour
authors: R
authors: R
authors: Duncan
authors: J
authors: J
authors: Strohalm
authors: J
authors: J
authors: Kopecek
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D002850:Chromatography, Gel; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007457:Iodine Radioisotopes; D008297:Male; D008970:Molecular Weight; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000178:Acrylamides; D000777:Anesthetics; D007457:Iodine Radioisotopes; D011108:Polymers; C032976:N-(2-hydroxypropyl)methacrylamide