Pharmacokinetics, disposition and metabolism of 546C88 (L-N^G-methylarginine hydrochloride) in rat and dog

Abstract

1. ¹⁴C-546C88 (¹⁴C-L-N^G-methylarginine hydrochloride) was administered to rat and dog as a single 5-min intravenous infusion at 1·7 mg/kg (20 mg/kg/h) to aid in the preclinical safety evaluation of the compound. 2. The distribution and elimination of parent compound from plasma was rapid in both species. 3. Drug-derived radioactivity was eliminated slowly. There was up to 39% of the dose retained in the carcasses at the end of the 7-day collection periods. The main route of elimination was as ¹⁴CO₂ in the expired air. Less than 8% of the dose was excreted in the urine, and < 5% in the faeces. 4. Drug derived radioactivity was widely distributed throughout the body with highest concentrations in tissues with a high protein turnover, such as glandular tissue and liver. 5. ¹⁴C-546C88 appeared to be eliminated primarily by metabolism and subsequent putative amino acid catabolism, resulting in retention of drug-derived radioactivity in tissues, and ultimate eliminationas ¹⁴CO₂ in the expired air. Potential routes of metabolism of 546C88 have been identified.