Steady-state pharmacokinetics of indobufen enantiomers in patients with obliterative atherosclerosis

Steady-state pharmacokinetics of indobufen (INDB) enantiomers administered as racemic INDB (rac-INDB) tablets and bleeding time were studied in patients. Two-hundred mg INDB tablets (Ibustrin) were administered twice daily for 7 days to obliterative atherosclerosis patients. Enantiospecific reversed phase (RP) HPLC with UV detection (lambda = 275 nm) was used for determination of INDB enantiomers in serum of patients. The ratio AUC(R):AUC(S) equalled 1.7 +/- 0.2 as a result of higher (-)-R-enantiomer serum levels. The (+)-S-enantiomer was more rapidly eliminated (oral clearance, CI = 1.1 +/- 0.3 L/h) than its (-)-R-antipode (Cl = 0.7 +/- 0.2 L/h). Therefore, the mean steady-state levels of (-)-R-enantiomer (13.5 +/- 3.8 mg/L) exceeded those of its (+)-S-enantiomer (7.8 +/- 1.8 mg/L). Furthermore, half-life (t(1/2)) was significantly shorter for (+)-S-INDB (t(1/2) = 4.5 +/- 1.2 h as compared to (-)-R-INDB (t(1/2) = 7.4 +/- 2.4 h). However, no significant differences were observed in the respective V-d values. The bleeding time of patients was not significantly extended. The above pharmacokinetic data provide a rationale for potential future replacement of INDB racemic tablets with tablets of its (+)-S-enantiomer. Chirality 13:308-312, 2001. (C) 2001 Wiley-Liss, Inc.