PRELIMINARY PHARMACOKINETIC STUDY OF IBUPROFEN ENANTIOMERS AFTER ADMINISTRATION OF A NEW ORAL FORMULATION (IBUPROFEN ARGININE) TO HEALTHY MALE-VOLUNTEERS

The pharmacokinetics of ibuprofen enantiomers were investigated in a c rossover study in which seven healthy male volunteers received single oral doses of 800 mg racemic ibuprofen as a soluble granular formulati on (sachet) containing L-arginine (designated trade name: Spedifen(R)) , 400 mg (-)R-ibuprofen arginine or 400 mg (+)S-ibuprofen arginine. Pl asma levels of both enantiomers were monitored up to 480 minutes after drug intake using an enantioselective analytical method (HPLC with ul traviolet detection) with a quantitation limit of 0.25 mg/l. Substanti al inter-subject variability in the evaluated pharmacokinetic paramete rs was observed in the present study, After (+)S-ibuprofen arginine, t he following mean pharmacokinetic parameters +/-SD were calculated for (+)Sibuprofen: t(max) 28.6 +/- 28.4 min; C-max 36.2 +/- 7.7 mg/l; AUC 86.4 +/- 14.9 mg.h/l; t(1/2) 105.2 +/- 20.4 min. After (-)R-ibuprofen arginine, the following mean pharmacokinetic parameters were calculat ed for (+)S- ibuprofen and (-)R-ibuprofen, respectively: t(max) 90.0 /- 17.3 and 50.5 +/- 20.5 min; C-max 9.7 +/- 3.0 and 35.3 +/- 5.0 mg/l ; AUC 47.0 +/- 17.2 and 104.7 +/- 27.7 mg.h/l; t(1/2) 148.1 +/- 63.6 a nd 97.7 +/- 23.3 min. After racemic ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)-S and (-)R-ibu profen, respectively: t(max) 30.7 +/- 29.1 and 22.9 +/- 29.8 min.; C-m ax 29.9 +/- 5.6 and 25.6 +/- 4.4 mg/l; AUC 105.1 +/- 23.0 and 65.3 +/- 15.0 mg.h/l; t(1/2) 136.6 +/- 20.7 and 128.6 +/- 45.0 min. T-max valu es of S(+)- and (-)R-ibuprofen after a single dose of 400 mg of each e nantiomer did not differ significantly from the corresponding paramete rs obtained after a single dose of 800 mg of racemic ibuprofen arginin e, indicating that the absorption rate of (-)R- and (+)S-ibuprofen is not different when the two enantiomers are administered alone or as a racemic compound. An average of 49.3 +/- 9.0% of a dose of the ( -)R-i buprofen arginine was bioinverted into its antipode during the study p eriod (480 minutes post-dosing). The percent bioinversion during the f irst 30 minutes after (-)R-ibuprofen arginine intake averaged 8.1 +/- 3.9%. The mean AUC of (+)Sibuprofen calculated after 800 mg racemic ib uprofen arginine (105.1 +/- 23.0 mg.h/l) was lower than the mean AUC v alue obtained by summing the AUCs of (+)Sibuprofen after administratio n of 400 mg (+)Sibuprofen arginine and 400 mg (-)R-ibuprofen arginine (133.4 +/- 26.6 mg.h/l). In conclusion, the administration of Spedifen (R) resulted in very rapid absorption of the (+)S-isomer (eutomer) wit h t(max) values much lower than those observed for this isomer when co nventional oral solid formulations such as capsules or tablets of race mic ibuprofen are administered. This characteristic is particularly fa vourable in those conditions in which a very rapid analgesic effect is required. Chirality 9:297-302, 1997. (C) 1997 Wiley-Liss, Inc.