PHARMACOKINETICS AND PHARMACODYNAMICS OF DERMATAN SULFATE AFTER INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATION TO HEALTHY-VOLUNTEERS

The pharmacokinetics and pharmacodynamics of dermatan sulfate (DS) was investigated in healthy volunteers (two groups, namely group A: 6 sub jects, group B: 8 subjects). The subjects of group A received 100 mg o f DS both i.v. and i.m. and the subjects of group B received 400 mg of DS both i.v. and i.m. in two different days. The resulting anticoagul ant activities were assessed by the activated partial thromboplastin t ime (aPTT) and the pharmacokinetic parameters were calculated from the plasma concentrations of DS measured by a chromogenic assay. The plas ma concentrations of DS were fitted by linear and non-linear eliminati on models (i.e. assuming that the drug elimination follows Michaelis-M enten kinetics). Some evidence of non-linear kinetics was given by the observation that the mean terminal half-life and clearance estimated by the linear model were not independent of the i.v. dose (0.83+/-0.1 and 1.74+/-0.21 hours and 4.94+/-0.64 and 2.67i+/-0.27 I/h after 100 a nd 400 mg i.v. respectively. Moreover the mean half-lives estimated af ter i.m. administrations were much higher than the values estimated af ter the i.v. dose (2.03+/-0.74 and 3.54+/-1.3 hours after 100 and 400 mg) and linear models failed to fit simultaneously the DS plasma conce ntrations after both the administration routes. Using the linear model , the mean drug bioavailabilty after i.m. administration was estimated to be about 30% and 80% after the 100- and the 400-mg dose respective ly. Assuming a complete drug bioavailabilty after i.m. administration, the non-linear elimination model interpolated well with the DS plasma concentrations, fitting simultaneously the i.v. and the i.m. data. No side-effects were recorded during the study, and routine biochemical and haematological parameters remained unchanged at the end of the stu dy.