Enantioselectivity in the steady-state pharmacokinetics of metoprolol in hypertensive patients

In the present study we investigated the enantioselectivity in the pharmaco kinetics of metoprolol administered in a multiple-dose regimen as the racem ate. The study was conducted on 10 patients of both sexes with mild to seve re essential hypertension, aged 28 to 76 years, with normal hepatic and ren al function and phenotyped as extensive metabolizers of debrisoquine (urine debrisoquine to 4-hydroxydebrisoquine ratios of 0.28 to 6.56). The patient s were treated with racemic metoprolol (two 100 mg tablets every 24 h) for 7 days. Serial blood samples were collected at times zero, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 22, and 24 h and urine at each 6 h period until 24 h after metoprolol administration. The plasma concentrations of the (-) -(S)- and (+)-(R)-metoprolol enantiomers were determined by HPLC using a ch iral stationary phase (Chiralpak AD, 4.6 x 250 mm) and fluorescence detecti on. The enantiomeric ratios differing from one were evaluated by the paired t test and the results are reported as means (95% CI). No differences were observed between metoprolol enantiomers in half-lives and absorption, dist ribution and elimination rate constants. However, the following differences (p < 0.05) were observed between the (-)-(S) and (+)-(R) enantiomers: maxi mum plasma concentration, C-max, 179.99 (123.33-236.64) versus 151.30 (95.0 4-207.57) ng/mL; area under the plasma concentration versus time curve, AUC (0-24)(SS), 929.85 (458.02-1401.70) versus 782.11 (329.80-1234.40) ng h/mL; apparent total clearance; Cl-T/f; 1.70 (0.79-2.61) versus 2.21 (1.06-3.36) L/h/kg, apparent distribution volume, Vd/f, 10.51 (6.35-14.68) versus 13.8 0 (6.93-20.68) L/kg, and renal clearance, Cl-R, 0.06 (0.05-0.08) versus 0.0 7 (0.05-0.09) L/kg. The enantiomeric ratios AUC((-)-(S))/AUC((+)-(R)) range d from 1.14 to 1.44, with a mean of 1.29. The data obtained demonstrate ena ntioselectivity in the kinetic disposition of metoprolol, with plasma accum ulation of the pharmacologically more active (-)-(S)-metoprolol enantiomer in hypertensive patients phenotyped as extensive metabolizers of debrisoqui ne. (C) 1999 Wiley-Liss, Inc.