Effects of oral administration of a high-molecular-weight crosslinked polyacrylate in rats.

Oral feeding studies of a crosslinked, high-molecular-weight polyacrylate polymer (PA) were conducted to (1) characterize the biological effects following exposure to either 0, 300, 1000, or 3000 mg PA/kg/day for 93 days; (2) characterize the fecal and urinary mineral excretion at these same dose levels; and (3) monitor the absorption, distribution, and excretion (ADE) of radiolabeled PA following a single oral exposure. The subchronic study results indicate that dietary intake of up to 3000 mg/kg/day PA had no adverse histopathology, hematology, body weight, or clinical chemistry effects in rats. Dietary exposure to PA did, however, result in an elevation in urinary excretion of sodium and phosphorus, whereas excretion of magnesium, calcium, and potassium was lowered. A more detailed study demonstrated that although the urinary excretion of these minerals was changed, total recovery of the minerals (feces + urine), except for sodium, was not different from that for controls. An increase in sodium excretion was expected since PA was in the form of a sodium salt. The ADE studies following a single oral dose of PA indicate that the majority of dosed PA (91.9%) was excreted in the feces. As expected, a small percentage (approximately 3.5%) was absorbed, possibly metabolized, and excreted. In summary, the oral administration of high levels of PA resulted in (1) no histological, hematological, or clinical chemistry changes; (2) no alteration in the overall mineral excretion (feces + urine) with the exception of sodium; and (3) primarily fecal excretion of orally administered PA.

Metabolism of atenolol in man.

1. The disposition and metabolism of 1-(4-carbamoyl[14C]methylphenoxy)-3-isopropylaminopan-2-ol (atenolol, Tenormin) has been studied in man following oral and intravenous doses. 2. Approx. 50% of an oral dose was eliminated in urine; the major radiolabelled component was atenolol (approx. 90%). Faecal extracts also contained largely unchanged atenolol, with small amounts of more polar metabolites. Biliary excretion of atenolol and its metabolites is not a major route of elimination in man. Metabolism of the compound is not extensive and route-dependent modes of metabolism do not appear to complicate the position. 3. Atenolol appeared to be the only major radiolabelled component in blood. 4. Oral doses of atenolol are incompletely absorbed (range 46-62%), even when formulated as a solution. 5. 1-[4-(C-Carbamoylhydroxymethyl)phenoxy]-3-isopropylaminopropan-2-ol was a minor urinary metabolite, which has only one tenth the activity of the parent compound as a beta-adrenergic blocking agent in the rat. 6. Pharmacological activity in man appears to be due to atenolol alone.

Disposition and metabolism of atenolol in animals.

1. The disposition of [14C]atenolol (1-[4-carbamoylmethyl[U-14C]phenoxy]-3-isopropylaminopropan-2-ol, Tenormin) has been studied in five species. 2. In the dog, absorption of oral doses of atenolol was virtually complete, and elimination occurred largely via the kidney. In all other species absorption even from aq. soln. was incomplete. 3. Biliary excretion in the rat and dog was minimal. 4. In all species, the major 14C component of 0-24 h urine was atenolol. The pattern of metabolites was similar, showing quantitative rather than qualitative differences. 5. The one significant minor metabolite detected in microsomal preparations and in urine arises by hydroxylation at the methylene carbon of the carbamoylmethyl group. This metabolite has only one tenth of the activity of the parent compound as a beta-adrenergic blocking agent in the rat. 6. The pharmacological activity of the drug appears to be due to the parent compound alone.