Summary
The basic law in nephropharmacology states that pharmacokinetic parameters depend linearly on renal function. Few exceptions to linear dependence have been reported, e.g. substances with saturable tubular reabsorption or secretion.
A further example is cyclosporin, which was found to be eliminated according to log-concave nonlinear kinetics in 3 patients with hepatotoxicity after kidney transplantation. The nonlinear cyclosporin kinetics were computer-fitted to the integrated forms of the 1-exp function and the Michaelis-Menten equation by nonlinear regression analysis. The same maximal velocity (Vmax = 23 ng ml−1 h−1) and Michaelis constant (Km = 686 ng ml−1) were calculated for cyclosporin when applying either the 1-exp function or the Michaelis-Menten equation.
The nonlinear elimination of cyclosporin, however, was described even more closely by the 1-exp function than by the Michaelis-Menten equation.
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References
Briggs GE, Haldane JBS (1925) A note on the kinetics of enzyme action. Biochem J 19: 338–339
Dettli L (1974) Drug dosage and renal disease. Clin Pharmacol Therap 16: 51–54
Gloff CA, Benet LZ (1989) Differential effects of the degree of renal damage on p-aminohippuric acid and inulin clearances in rats. J Pharmacokinet Biopharm 17: 169–177
Haegele KD, Huebert ND, Ebel M, Tell GP, Schechter PJ (1988) Pharmacokinetics of vigabatrin: implications of creatinine clearance. Clin Pharmacol Therap 44: 558–565
He YL, Tanigawara Y, Kamiya A, Hori R (1991) Moment analysis of drug disposition in kidney. VI: assessment of in vivo transmembrane transport of p-aminohippurate in tubular epithelium. J Pharmacokinet Biopharm 19: 667–690
Hill CM, Waight RD, Bardsley WG (1977) Does any enzyme follow the Michaelis-Menten equation? Molec Cell Biochem 15: 173–178
Keller F, Koeppe P, Emde C (1984) Exponential function of chymotrypsin action. Enzyme 31: 39–44
Keller F, Emde C, Schwarz A (1988) Exponential function for calculating saturable enzyme kinetics. Clin Chem 34: 2486–2489
Keller F, Giehl M (1990) Saturation-type exponential function with a deceleration term for calculating nonlinear kinetics. Naturwissenschaften 77: 435–436
Keller F, Kunzendorf U, Walz G, Schwarz A, Offermann G (1990) Slow accumulation of cyclosporin metabolites as measured by specific and nonspecific cyclosporin RIA. Int J Clin Pharmacol Therap Toxicol 28: 167–175
Koeppe P, Hamann C (1980) A program for non-linear regression analysis tobe used on desk-top computers. Comput Progr Biomed 12: 121–128
Michaelis L, Menten ML (1913) Die Kinetik der Invertinwirkung. Biochem Z 49: 333–369
Prescott LF, McAuslane JAN, Freestone S (1991) The concentration-dependent disposition and kinetics of inulin. Eur J Clin Pharmacol 40: 619–624
Rakhit A, Radensky P, Szerlip HM, Kochak GM, Audet PR, Hurley ME, Feldman GM (1988) Effect of renal impairment on disposition of pentopril and its active metabolite. Clin Pharmacol Therap 44: 39–48
Tsao C, Greene P, Odlind B, Brater DC (1991) Pharmacokinetics of recombinant human superoxide dismutase in healthy volunteers. Clin Pharmacol Therap 50: 713–720
Weber W, Nitz M, Looby M (1990) Nonlinear kinetics of the thiamine cation in humans: saturation of nonrenal clearance and tubular reabsorption. J Pharmacokinet Biopharm 18: 501–523
Weber W, Toussaint S, Looby M, Nitz M, Kewitz H (1991) System analysis in multiple dose kinetics: evidence for saturable tubular reabsorption of the organic cation n-methylnicotinamide in humans. J Pharmacokinet Biopharm 19: 553–574
Wong JTF (1975) Kinetics of enzyme mechanisms. Academic Press, London, pp 1–14
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Keller, F., Erdmann, K. & Giehl, M. Nonlinear kinetics and the 1-exp function in nephropharmacology. Eur J Clin Pharmacol 44 (Suppl 1), S27–S30 (1993). https://doi.org/10.1007/BF01428388
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DOI: https://doi.org/10.1007/BF01428388