Summary
The oxidative metabolism of tolbutamide was studied in 13 healthy subjects of known debrisoquine phenotype. Three were poor (PM) and ten were extensive (EM) metabolisers of debrisoquine.
The mean values for total plasma clearance, elimination half-life, and metabolic clearance were 0.26 ml·min−1·kg−1, 3.4 h, and 0.17 ml·min−1. kg−1 in PM subjects and 0.22 ml·min−1·kg−1, 4.3 h and 0.15 ml·min−1·kg−1 in EM subjects. Total urinary recovery (% of dose) and ratio of hydroxy- to carboxytolbutamide were 69.4% and 0.219 respectively in PM subjects and 70.9% and 0.226 in EM subjects. There were no statistically significant differences between EM and PM metabolisers for any of these parameters. In addition there was no correlation between the debrisoquine metabolic ratio and tolbutamide urinary metabolite recovery or plasma clearance.
These data indicate that hydroxylation of debrisoquine and tolbutamide are not catalyzed by the same enzyme.
The ratio of hydroxy- to carboxytolbutamide in our subjects, and in other recent studies, suggests that some previous publications were inaccurate and their conclusions about the genetic control of tolbutamide metabolism were incorrect.
Similar content being viewed by others
References
Eichelbaum M, Spannbrucker N, Steinke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man: A new pharmacogenetic defect. Eur J Clin Pharmacol 16: 183–187
Eichelbaum M, Bertilsson L, Sarve J, Zekoru C (1982) Polymorphic oxidation of sparteine and debrisoquine: Related pharmacogenetic entities. Clin Pharmacol Ther 31: 184–186
Idle JR, Sloan TP, Smith RL, Wakile LA (1979) Application of the phenotyped panel approach to the detection of polymorphism of drug oxidation in man. Br J Pharmacol 66: 430P-431P
Jackson JIS, Bressler R (1981) Clinical Pharmacology of sulphonylurea hypoglycaemic agents: Part 1. Drugs 22: 211–245
Jackson PR, Tucker GT, Lennard MS, Woods HF (1986) Polymorphic drug oxidation: Pharmacokinetic basis and comparison of experimental indices. Br J Clin Pharmacology 22: 541–550
Mahgoub A, Idle JR, Dring G, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2: 584–586
Miners JD, Wing LMH, Birkett DJ (1985) Normal metabolism of debrisoquine and theophylline in a slow tolbutamide metaboliser. Aust NZJ Med 15: 348–349
Peart GF, Boutagy J, Shenfield GM (1986) Debrisoquine oxidation in an Australian population. Br J Clin Pharmacol 21: 465–471
Prine Evans DA, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 17: 102–105
Prine Evans DA (1986) Therapy. Ethnic difference in reactions to drugs and xenobiotics. Prog Clin Biol Res 214: 491–526
Scott J, Poffenbarger P (1979) Pharmacokinetics of tolbutamide metabolism in humans. Diabetes 28: 41–51
Shibasaki J, Konishi R, Takayoshi J, Veki T (1979) Drug absorption, metabolism and excretion IX. Some new aspects of pharmacokinetics of tolbutamide in rabbits. Chem Pharmacol Bull 21: 1754–63
Thomas RC, Ikeda BJ (1966) The metabolic fate of tolbutamide in man and the rat. J Med Chem 9: 507–510
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Peart, G.F., Boutagy, J. & Shenfield, G.M. Lack of relationship between tolbutamide metabolism and debrisoquine oxidation phenotype. Eur J Clin Pharmacol 33, 397–402 (1987). https://doi.org/10.1007/BF00637637
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00637637