Abstract
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 100mg/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 μg/ml. This IC50 is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 μg/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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
J. R. Lewis. New antirheumatic agents. Fenoprofen calcium (Nalfon), Naproxen (Naprosyn), and Tolmetin sodium (Tolectin). J. Am. Med. Assoc. 237:1260–1261 (1977).
R. J. Taylor and J. J. Salata. Inhibition of prostaglandin synthetase by tolmetin (tolectin, McN-2559), a new non-steroidal anti-inflammatory agent. Biochem. Pharmacol. 25:2479–2484 (1976).
M. L. Selley, J. Glass, E. J. Triggs, and J. Thomas. Pharmacokinetic studies of tolmetin in man. Clin. Pharmacol. Ther. 17:599–605 (1975).
S. H. Dromgoole, D. E. Furst, R. K. Desiraju, R. K. Nayak, M. A. Kirschenbaum, and H. E. Paulus. Tolmetin kinetics and synovial fluid prostaglandin E levels in rheumatoid arthritis. Clin. Pharmacol. Ther. 32:371–377 (1982).
D. E. Furst, S. H. Dromgoole, R. K. Desiraju and H. E. Paulus. Clinical pharmacology of tolmetin: Comparisons in rheumatoid arthritis patients and normal volunteers. J. Clin. Pharmacol. 23:329–335 (1983).
G. Levy. Mechanism-based pharmacodynamic modeling [Commentary]. Clin. Pharmacol. Ther. 56:356–358 (1994).
V. Granados-Soto, F. J. Flores-Murrieta, F. J. López-Muñoz, L. A. Salazar, J. E. Villarreal and G. Castañeda-Hernández. Relationship between paracetamol plasma levels and its analgesic effect in the rat. J. Pharm. Pharmacol. 44:741–744 (1992).
V. Granados-Soto, F. J. López-Muñoz, G. Castañeda-Hernández, L. A. Salazar, J. E. Villarreal, and F. J. Flores-Murrieta. Characterization of the analgesic effects of paracetamol and caffeine combinations in the pain-induced functional impairment model in the rat. J. Pharm. Pharmacol. 45:627–631 (1993).
V. Granados-Soto, F. J. López-Muñoz, E. Hong, and F. J. Flores-Murrieta. Relationship between pharmacokinetics and the analgesic effect of ketorolac in the rat. J. Pharmacol. Exp. Ther. 272:352–356 (1995).
F. J. López-Muñoz, L. A. Salazar, G. Castañeda-Hernández, and J. E. Villarreal. A new model to assess analgesic activity: Pain-induced functional impairment in the rat (PIFIR). Drug Dev. Res. 28:169–175 (1993).
L. B. Sheiner. The population approach to pharmacokinetic data analysis: Rationale and standard data analysis methods. Drug Metab. Rev. 15:153–171 (1984).
D. M. Flores-Acevedo, F. J. Flores-Murrieta, G. Castañeda-Hernández and F. J. López-Muñoz. Potentiation of the analgesic effect of tolmetin, a potent non-steroidal anti-inflammatory drug, by caffeine in the rat. Pharm. Sci. 1:441–444 (1995).
N. L. Dayneka, V. Garg, and W. J. Jusko. Comparison of four basic models of indirect pharmacodynamic responses. J. Pharmacokin. Biopharm. 21:457–478 (1993).
W. J. Jusko and H. C. Ko. Physiologic indirect response models characterize diverse types of pharmacodynamic effects. Clin. Pharmacol. Ther. 56:406–419 (1994).
The Committee for Research and Ethical Issues of the International Association for the Study of Pain. Ethical standards for investigation of experimental pain in animals. Pain 9:141–143 (1980).
NONMEM User's Guides, S. L. Beal and L. B. Sheiner (eds.), NONMEM Project Group, University of California, San Francisco. San Francisco, 1992.
J. R. Wade, A. W. Kelman, C. A. Howe, and B. Whiting. Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis. J. Pharmacokin. Biopharm. 21:209–222, 1993.
N. H. G. Holford and L. B. Sheiner. Understanding the dose-effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models. Clin. Pharmacokin. 6:429–453 (1981).
A. Dray and J. N. Wood. Nonopioid molecular signaling mechanisms involved in nociception and antinociception. In A. I. Basbaum and J.-M. Besson (eds.), Towards a New Pharmacotherapy of Pain, Wiley, New York, 1991, pp. 21–34.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Flores-Murrieta, F.J., Ko, H.C., Flores-Acevedo, D.M. et al. Pharmacokinetic–Pharmacodynamic Modeling of Tolmetin Antinociceptive Effect in the Rat Using an Indirect Response Model: A Population Approach. J Pharmacokinet Pharmacodyn 26, 547–557 (1998). https://doi.org/10.1023/A:1023273100270
Published:
Issue Date:
DOI: https://doi.org/10.1023/A:1023273100270