Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: a population approach.

The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2 or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50 of 9.22 micrograms/ml. This IC50 is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 micrograms/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.

Pharmacokinetics of ketorolac in children after abdominal surgery.

The pharmacokinetics of 2 doses of intravenous ketorolac (0.5 and 0.9 mg x kg-1) were studied in 14 children (age 2-8 years). A single dose of the drug was injected into the dorsum vein of one hand. Blood samples were collected at regular time intervals for 6 hours. Serum ketorolac concentrations were assayed using a high pressure liquid chromatography method. Pharmacokinetic values were estimated by a nonlinear computer program. The distribution volume (Vdarea), the total clearance (Cltotal), and elimination half-life (t1/2 beta) were similar in both groups of children who either received 0.5 or 0.9 mg x kg-1 of ketorolac. The estimated geometric mean Vdarea, Cltotal, and t1/2 beta ratios (95% CI in parentheses) for 0.9 mg x kg-1:0.5 mg x kg-1 were 1.24 (0.82, 1.50), 1.14 (0.88, 1.23), and 1.083 (0.40, 1.81), respectively. The pharmacokinetic parameters found in this study are different from those found by other authors in adult subjects.

Determination of ketorolac in blood and plasma samples by high-performance liquid chromatography.

A new method for determination of ketorolac in blood or plasma samples by reversed-phase high-performance liquid chromatography has been developed. The method includes a double extraction with diethyl ether and detection by absorbance at 313 nm. Quantitation was performed by height ratios of ketorolac and the internal standard (sodium tolmetin). Detection limit of the method was 3 ng/ml using 1 ml of plasma and 10 ng/ml using 0.2 ml of blood. The method is linear in the range of concentrations typically obtained after therapeutic doses of the drug, has the advantages of using low volume of body fluid and the internal standard used is commercially available. Those characteristics allow us to conclude that this method is suitable for pharmacokinetic or drug monitoring studies.

Comparative bioavailability of two oral formulations of ketorolac tromethamine: Dolac and Exodol.

The bioavailability of ketorolac after administration of two oral formulations containing 10 mg of ketorolac tromethamine, Exodol and Dolac, to 12 healthy Mexican volunteers was compared. Subjects received both formulations according to a randomized crossover design and blood samples were drawn at selected times during 24 h. Ketorolac plasma concentrations were determined by HPLC and individual plasma-concentration-against-time curves were constructed. Maximal plasma concentration and AUC0-24 values were compared by analysis of variance followed by Westlake's confidence interval test. 90% confidence limits ranged from 80 to 125% for Cmax and from 85 to 118% for AUC0-24. It is concluded that the two assayed formulations are bioequivalent.