Pharmacokinetics in humans

In most pharmacokinetic studies of nimesulide in healthy volunteers and different patient populations, the concentrations of the parent compound and of the main metabolite, i.e., the 4'-hydroxy derivative (M1), in plasma and urine were determined by HPLC [18-28]. Sample handling involves the extraction of nimesulide, M1 and the internal standard from acidified biological samples using organic solvents. After solvent evaporation, the extract residue is dissolved in the mobile phase and analysed by reverse phase HPLC with UV/VIS detection. Accuracy and precisions evaluated in plasma and urine samples for nimesulide and M1 are satisfactory for application of the methods to the analysis of biological samples in pharmacokinetic studies. The lower limit of quantitation (LLOQ) ranges from 25-50 ng/ml. A column-switching technique was also introduced [22]. This involves the direct injection of deproteinised plasma samples into an ODS extraction column, followed by chromatographic separation of nimesulide, M1 and the internal standard on a C18-analytical column. UV detection is made at 330 nm.

Absorption

The favourable physical-chemical properties of nimesulide presented earlier in this chapter may explain the good oral bioavailability of this drug, evaluated in several studies in healthy individuals [23-26]. Nimesulide is rapidly absorbed from the gastrointestinal tract and the rate and the extent of nimesulide absorption are similar whether the drug is administered in tablet, suspension or granular form. Indeed, similar maximum concentration (Cmax), time to Cmax (tmax), and AUC values have been estimated after oral administration of different formulations to fasting healthy individuals (Tab. 6).

After oral administration of a 100 mg dose to healthy fasting subjects, a mean Cmax of 2.86-6.50 mg/L was achieved within 1.22-2.75 h [19, 23-30]. Nimesulide concentrations of approximately 25-80% of the Cmax appeared at the first sampling time, 30 min after administration. Pharmacological effectiveness appears to be exhibited earlier than time to Cmax, from 30 to 60 min after administration [31, 32]. In 100 hospitalised children with acute upper respiratory tract infections and fever (body temperature 38.5 °C), the mean body temperature was decreased significantly 1 h after administration of a single dose of nimesulide suspension 5 mg/kg [31]. In the same study, the tmax in paediatric patients receiving nimesulide 50 mg (granules) was close to 2 h.

No studies of intravenously administered nimesulide were performed in this study and, therefore, the absolute bioavailability (F) of oral nimesulide has not been evaluated. However, the extent of oral nimesulide absorption may be deduced from mass balance studies (Tab. 7).

Table 6 - Pharmacokinetic parameters for nimesulide in healthy adult volunteers after single and multiple doses. Mean values [3]

No. subjects and gender

Study design

Dosage form

(mg/L)

^max

^m ax (h)

0 0

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