Naphthoxylactic acid after single and long-term doses of propranolol.

Abstract

The disposition of naphthoxylactic acid (NLA) and propranolol was determined after single intravenous and oral doses of propranolol in 5 subjects and during long‐term therapy in 8 hypertensive patients. The area under the plasma concentration/time curve (AUC) of NLA exceeded that of propranolol twofold after an intravenous 4‐mg dose of propranolol but tenfold after single oral 20‐mg and 80‐mg doses, indicating a high degree of presystemic formation of NLA. The time to peak concentration (1.5 to 2 hr) and the plasma half‐life of NLA (3.1 to 4.2 hr) were in the same range as for propranolol. A two‐ to threefold accumulation of NLA in plasma was indicated after chronic propranolol therapy. Whereas plasma concentrations and urinary excretion of NLA increased linearly with dose on long‐term propranolol dosage, there was a nonlinear relationship between propranolol plasma levels and dose. This resulted in a markedly reduced NLA/propranolol plasma level ratio with increasing doses (from 10 to 28 at a daily 80‐mg propranolol dose to about 3 at a daily 960‐mg dose). The urinary excretion of NLA accounted for about 14% of the propranolol dose over the dose range studied. The finding that the renal clearance of NLA (18 to 54 ml/min) and plasma levels were dependent on glomerular filtration rate (GFR) indicates that renal elimination is the main determinant of total body clearance of NLA and that it may accumulate strikingly in patients with severe renal disease.