Effect of dose and uremia on plasma and urine profiles of propranolol metabolites

The relationship between plasma levels of 4 propranolol metabolites—naphthoxylactic acid (NLA), 4‐hydroxypropranolol (4‐OH), naphthoxy acetic acid (NAA), and propranolol glycol (PG)—and propranolol plasma levels was determined in healthy, adult male subjects after increasing single oral doses of propranolol. NLA was present at plasma levels 6 to 25 times that of propranolol. More than 90% of circulating NLA was in the plasma fraction, where it was 95% protein bound. The ratio of plasma concentrations of the pharmacologically active metabolite 4‐OH to propranolol approached unity 0.5 hr after propranolol, 160 mg or 320 mg orally, but fell rapidly. Plasma levels of NAA were in the same range as propranolol, especially as time progressed. PG circulated at plasma levels less than 12% of propranolol. As oral doses of propranolol were increased from 20 to 320 mg, there was a decrease in intrinsic plasma clearance (Cl i ) from 425 to 200 l/hr. Half‐life rose from 3 to 5 hr. Urinary recovery of 4‐OH fell as Cl i rose. Urinary recovery of propranolol conjugates, NLA, and N ‐desisopropylpropranolol (NDIPP) rose as Cl i fell. Our results suggest that naphthalene ring oxidation of propranolol represents a high‐affinity low‐capacity enzymatic pathway(s) that plays an important role in the extensive hepatic extraction of propranolol after small doses orally. Plasma NLA and plasma NAA were determined before and after hemodialysis in 14 uremic patients receiving long‐term propranolol therapy. Mean plasma NLA was 4,372 ng/ml, and mean plasma NAA level was 238 ng/ml when mean plasma propranolol level was 15 ng/ml. Clinical Pharmacology and Therapeutics (1980) 27 , 744–755; doi: 10.1038/clpt.1980.105