Nonlinear accumulation of propranolol enantiomers

The accumulation of (+)- and (-)-propranolol was investigated in nine subjects who received 160 mg of racemic propranolol as a single dose and then once daily for 7 days. The serum concentrations of propranolol enantiomers were measured by h.p.l.c. using a novel chiral stationary phase allowing direct resolution of underivatized propranolol. The (+)-propranolol AUC increased from 412 +/- 223 ng ml-1 h after single doses (0-infinity) to 584 +/- 279 ng ml-1 h at steady-state (0-24 h) (P less than 0.05). Similarly, (-)-propranolol AUC increased from 609 +/- 304 to 777 +/- 370 ng ml-1 h (P less than 0.05). The AUC ratio (-)/(+) was 1.52 +/- 0.36 and 1.32 +/- 0.17 after single doses and steady-state, respectively (P greater than 0.05). Therefore, nonlinear accumulation occurs with both enantiomers although there is a trend for the (-)/(+) ratio to decrease at steady-state.