Summary
Plasma concentration-time data for benzoic and hippuric acids and urinary excretion-time data for hippuric acid were analyzed simultaneously after oral doses of 40, 80 or 160 mg/kg sodium benzoate administered at least one week apart to 6 healthy subjects.
The mean AUCs of benzoic acid after the doses of 80 and 160 mg/kg of sodium benzoate were 3.7- and 12.0-times greater, respectively, than after 40 mg/kg. However, the mean AUC of hippuric acid was roughly proportional to the benzoate doses. The observed data were explained by a one-compartment model with first-order rate absorption and Michaelis-Menten elimination of benzoic acid, together with a one-compartment model with first-order elimination for hippuric acid.
Although the maximum rate of biotransformation of benzoic acid to hippuric acid varied between 17.2 and 28.8 mg·kg−1·h−1 among the six individuals, the mean value (23.0 mg·kg−1·h−1) was fairly close to that provided by daily maximum dose (0.5 g·kg−1·day−1) recommended in the treatment of hyperammonaemia in patients with inborn errors of ureagenesis.
The individual maximum rate of metabolism can be estimated from the urinary excretion rate of hippuric acid 1.5 to 3 h after the single oral dose of 80 to 160 mg·kg−1 sodium benzoate. The justification of this concept requires further studies in patients with inborn errors of urea synthesis.
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References
Brusilow SW, Valle DL, Batshaw ML (1979) New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet II: 452–454
Quick AJ (1931) The conjugation of benzoic acid in man. J Biol Chem 92: 65–85
Chau NP (1976) Area-dose relationships in nonlinear models. J Pharmacokinet Biopharm 4: 537–551
Amsel LP, Levy G (1969) Drug biotransformation interaction in man II: A pharmacokinetic study of the simultaneous conjugation of benzoic and salicylic acids with glycine. J Pharm Sci 58: 321–326
Levy G, Tsuchiya T, Amsel LP (1972) Limited capacity for salicyl phenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man. Clin Pharmacol Ther 13: 258–268
Freiberg IK, West ES (1933) Glycine synthesis in pseudohypertrophic muscular dystrophy. J Biol Chem 101: 449–451
Bray HG, Thorpe WV, White K (1951) Kinetic studies of the metabolism of foreign organic compounds. Biochem J 48: 88–96
Oyanagi K, Kuniya Y, Tsuchiyama A, Nakao T, Owada E, Sato J, Ito K (1987) Nonlinear elimination of benzoate in patients with congenital hyperammonemia. J Pediatr 101: 634–636
Kubota K, Horai Y, Kushida K, Ishizaki T (1988) Determination of benzoic acid and hippuric acid in human plasma and urine by high-performance liquid chromatography. J Chromatogr 425: 67–75
Yamaoka K, Tanigawara Y, Nakagawa T, Uno T (1981) A pharmacokinetic analysis program (MULTI) for microcomputer. J Pharmacobiodyn 4: 879–885
Yamaoka K, Nakagawa T (1983) A nonlinear least squares program based on differential equations, MULTI (RUNGE), for microcomputers. J Pharmacobiodyn 6: 595–606
Sedman AJ, Wagner JG (1974) Importance of use of the appropriate pharmacokinetic model to analyze in vivo enzyme constants. J Pharmacokinet Biopharm 2: 161–173
Wagner JG (1973) Properties of the Michaelis-Menten equation and its integrated form which are useful in pharmacokinetics. J Pharmacokinet Biopharm 2: 161–173
Batshaw ML, Brusilow S, Waber L, Blom W, Brubakk AM, Burton BK, Cann HM, Kerr D, Mamunes P, Matalon R, Myerberg D, Schafer IA (1982) Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N Engl J Med 306: 1387–1392
Brusilow SW, Danney M, Waber LJ, Batshaw M, Burton B, Levitsky L, Roth K, McKeethren C, Ward J (1984) Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N Engl J Med 310: 1630–1634
Londesborough JC, Webster LT (1974) Fatty acyl-CoA syntheses. In: Boyer PO (ed), The enzymes, Academic Press, New York, pp 469–488
Levy G, Tsuchiya T (1972) Salicylate accumulation kinetics in man. N Engl J Med 287: 430–432
Needs CJ, Brooks PM (1985) clinical pharmacokinetics of the salicylates. Clin Pharmacokinet 10: 164–177
Griffith AD, Cyr DM, Egan SG, Tremblay GC (1989) Inhibition of pyruvate carboxylase by sequestration of coenzyme with sodium benzoate. Arch Biochem Biophys 269: 201–207
Maswoswe M, Cyr DM, Griffith AD, Tremblay GC (1986) The effect of sodium benzoate on ammonia toxicity in rats. Biochem Biophys Res Commun 138: 369–373
O'Connor JE, Costell M, Grisolia S (1987) The potentiation of ammonia toxicity by sodium benzoate is prevented by L-carnitine. Biochem Biophys Res Commun 145: 817–824
Michalak A, Qureshi IA (1990) Plasma and urinary levels of carnitine in different experimental models of hyperammonemia and the effect of sodium benzoate treatment. Biochem Med Metab Biol 43: 163–174
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This study was supported in part by a grant-in-aid from the Ministry of Human Health and Welfare, Tokyo, Japan
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Kubota, K., Ishizaki, T. Dose-dependent pharmacokinetics of benzoic acid following oral administration of sodium benzoate to humans. Eur J Clin Pharmacol 41, 363–368 (1991). https://doi.org/10.1007/BF00314969
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DOI: https://doi.org/10.1007/BF00314969