Microsoft Word - GER174BF

Letters to the Editor Letter from Dr. D.S. Sitar Sir: The study of drug disposition and effect as a function of the aging process is an increasingly important area of investigation. Cuny et al. (1) have recently reported results of their study concerning the effect of aging on salicylate disposition in this journal. Upon review of their publication, important deficiencies were noted which require comment. First, and most important, the model which they used to describe salicylate disposition is incorrect. In the dose administered to their volunteers, salicylate is eliminated by dose-dependent (Michaelis-Menten) kinetics (2-4). This fundamental error has resulted in inappropriate values for the elimination half-time by a factor of about 2. It has also resulted in a drastic underestimation of the apparent volume of distribution. If one plots the data from their publication on rectilinear graph paper, the plot is a classic example of a dose-dependent process. A detailed approach to optimal data analysis in this situation is available (5). Second, their calculation of ‘metabolic clearance’ is overestimated. This is due to a mathematical error, as they used t’/2 instead of kEL for this determination. Thus plasma clearance is overestimated by about one third. Use of the model independent formula ‘dose/ area under the plasma concentration versus time curve’ would have yielded values more in agreement with other publications (6). Third, the method of statistical analysis is inappropriate. A nonparametric test (Mann-Whitney U test) should have been used to eliminate the problem of differences in data variance due to effects of age. The use of the values of apparent volume of distribution and elimination rates as published in the report by Cuny et al. (1) for dosage regimen determinations would result in inappropriate use of salicylate. The above criticisms bring into question the significance of their findings with respect to effects of aging on salicylate disposition in man. References Cuny, G.; Royer, R.J.; Mur, J.M.; Serot, J.M.: Faure, G.; Netter, P.; Maillard, A., and Penin, F.: Pharmacokinetics of salicylates in elderly. Gerontology 25: 49-55 (1979). Levy, G.; Tsuchiya, T., and Amsel, L.P.: Limited capacity for salicyl phenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man. Clin. Pharmacol. Ther. 13: 258-268 (1972). Paulus, H.E.; Siegel, ML; Mongram, E.; Okun, R., and Calabro, J.J.: Variation of serum concentrations and half-life of salicylate in patients with rheumatoid arthritis. Arthritis Rheum. 14: 527 – 532(1971). Levy, G. and Tsuchiya, T.: Salicylate accumulation kinetics in man. New Engl. J. Med. 287: 430-432 (1972). Wagner, J.G.: Fundamentals of clinical pharmacokinetics, pp. 247-284 (Drug Intelligence Publications, Hamilton 1975).