Skip to main content
SpringerLink
Log in

Disposition of Antipyrine and Phenytoin Correlated with Age and Liver Volume in Man

  • Original Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Summary

The half-life and metabolic clearance rale (MCR) of antipyrine and phenytoin were determined in 14 young [mean age: 28.8 ± 8.3 (SD) years] and in 14 elderly [mean age: 83.5 ±7.1 (SD) years] subjects and correlated with liver volume, which was determined by ultrasonic scanning, to see if an age-dependent difference in drug metabolism could be explained by a reduced liver weight with age.

The size of the liver was smaller in the elderly subjects even when related to decreased body surface. A significant decrease in serum albumin in the elderly compared with the younger group was also noted. The half-life of antipyrine was significantly longer in the elderly than in the younger group, 756 ± 318 and 465 ± 110 minutes, respectively, and the MCR was correspondingly lower in the elderly even when calculated per litre of liver volume, 22.8 ± 7.8 and 36.3 ± 8.9ml/minute/L liver volume, respectively. No significant differences in the 2 age groups were found in half-life and total clearance of phenytoin, but a reduced free phenytoin clearance was demonstrated in the elderly (240 ± 92ml/minute/L liver volume) compared with the younger (325 ± 81 ml/minute/L liver volume) group. No significant correlation was found between liver volume and the half-life of antipyrine and phenytoin. However, a significant correlation was demonstrated between liver volume and MCR of antipyrine as well as between total and free clearance of phenytoin. No correlation was found between the half-lives of the 2 drugs, while a significant correlation existed between the clearance values.

It is suggested that the age-dependent reduction in drug clearance is due not only to a smaller liver volume, but is also a result of a reduced capacity of the liver microsomes per unit of liver in the elderly. With regard to age-dependent changes in drug metabolism, the protein binding of the actual drug has to be taken into consideration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Brien, J.F.; Inaba, T. and Kalow, W.: Comparative drug elimination in man — Diphenylhydantoin and amobarbital. European Journal of Clinical Pharmacology 9: 79–83 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Brodie, B.B.; Axelrod, J.; Soberman, R. and Levy, B.B.: Estimation of antipyrine in biological materials. Journal of Biological Chemistry 179: 25–29 (1949).

    PubMed  CAS  Google Scholar 

  • Castleden, C.M. and George, C.F.: The effect of ageing on the hepatic clearance of propranolol. British Journal of Clinical Pharmacology 7: 49–54 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Cunningham, J. L.; Bullen, M.F. and Price Evans, D.A.: The pharmacokinetics of acetanilide and diphenylhydantoin sodium. European Journal of Clinical Pharmacology 7: 461–466 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Cuny, G.; Royer, R.J.; Mur, J.M.; Serot, J.M.; Faure, G.; Netter. P.; Maillard, A. and Penin, F.: Pharmacokinetics of salicylates in the elderly. Gerontology 25: 49–55 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Davies, D.S.; Thorgeirsson, S.S.; Breckenridge, A. and Orme, M.: Interindividual differences in rates of drug oxidation in man. Drug Metabolism and Disposition 1: 411–417 (1973).

    PubMed  CAS  Google Scholar 

  • Halliwell, M.; Homeida, M. and Roberts, C.J.C.: Value of liver volume measurement in the study of antipyrine kinetics in liver disease. British Journal of Clinical Pharmacology 4: 393P–394P (1977).

    Article  Google Scholar 

  • Hansen, J.M.; Kristensen, M.; Skovsted, L. and Christensen, L.K.: Dicoumarol induced diphenylhydantoin intoxication. Lancet 2: 265–266 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Hayes, M.J.; Langman, M.J.S. and Short, A.H.: Changes in drug metabolism with increasing age. I. Warfarin binding and plasma proteins. British Journal of Clinical Pharmacology 2: 69–72 (1975a).

    PubMed  CAS  Google Scholar 

  • Hayes, M.J.; Langman, M J.S. and Short, A.H.: Changes in drug metabolism with increasing age. II Phenytoin clearance and protein binding. British Journal of Clinical Pharmacology 2: 73–79 (1975b).

    PubMed  CAS  Google Scholar 

  • Houghton, G.W.; Richeas, A. and Leighton, M.: Effects of age, height, weight and sex on serum concentration in epileptic patients. British Journal of Clinical Pharmacology 2: 251–256 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Johnsen, S.G.; Kampmann, J.P.; Bennett, E.P. and Jørgensen, F.S.: Enzyme induction by oral testosterone. Clinical Pharmacology and Therapeutics 20: 233–237 (1976)

    CAS  Google Scholar 

  • Jori, A.; DiSalle, E. and Quadri, A.: Rate of aminopyrine disappearance from plasma in young and aged humans. Pharmacology 8: 273–279 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Kadar, D.; Inaba, T.; Endrenyi, L.; Hohnson, G.E. and Kalow, W.: Comparative drug elimination capacity in man —glulethimide, amobarbital, antipyrine and sulfinpyrazone. Clinical Pharmacology and Therapeutics 14: 552–560 (1973).

    PubMed  CAS  Google Scholar 

  • Kampmann, J.P.; Mortensen, H.B.; Bach, B.; Waldroff, S; Kristensen, M. and Hansen, J.M.: Kinetics of propylthiouracil in the elderly. Acta Medica Scandinavica 624 (Suppl.): 93–98 (1979).

    PubMed  CAS  Google Scholar 

  • Kato, R.; Vassanelli, P.; Frontino, G. and Chiesara, E.: Variation in activity of liver microsomal drug-metabolising enzymes in rats in relation to age. Biochemical Pharmacology 13: 1037–1051 (1964)

    Article  PubMed  CAS  Google Scholar 

  • Klotz, U.; Avant, G.R.; Hoyumpa, A.; Schenker, S. and Wilkinson, G.R.: The effects of age and liver disease on the disposition and elimination of diazepam in adult man. Journal of Clinical Investigation 55: 347–359 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Lumholtz, B.; Siersbaek-Nielsen, K.; Skovsted, L.; Kampmann, J.P. and Hansen, J.M.: Sulfamethizole induced inhibition of diphenylhydantoin, tolbutamide and warfarin metabolism. Clinical Pharmacology and Therapeutics 17: 731–734 (1975).

    PubMed  CAS  Google Scholar 

  • O’Malley, K.; Crooks, J.; Duke, E. and Stevenson, I.H.: Effects of age and sex on human drug metabolism. British Medical Journal 3: 607–609 (1971).

    Article  PubMed  Google Scholar 

  • Pirttiaho, H.I.; Sotaniemi, E.A.; Ahokas, J.T. and Pitkänen, U.: Liver size indices of drug metabolism in epileptics. British Journal of Clinical Pharmacology 6: 273–278 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen, S.N.: Liver volume determination by ultrasonic scanning. Danish Medical Bulletin 25: 1–48 (1978)

    PubMed  CAS  Google Scholar 

  • Rasmussen, S.N.; Hansen, J.M.; Kampmann, J.P.; Skovsted, L. and Bach, B.: Drug metabolism in relation to liver volume and age. Scandinavian Journal of Gastroenterology 11 (Suppl. 38): 82 (1976).

    Google Scholar 

  • Roberts, C.J.C.; Jackson, L.; Halliwell, M. and Branch, R.A.: The relationship between liver volume, antipyrine clearance and indocyanin green clearance before and after phenobarbitone administration in man. British Journal of Clinical Pharmacology 3: 907–913 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Rodkey, F.L: Direct spectro-photometric determination of albumin in human serum. Clinical Chemistry 11: 478–487 (1965).

    PubMed  CAS  Google Scholar 

  • Sato, T.; Miwa, T. and Tauchi, H.: Age changes in the human liver of the different races. Geronlologia 16: 368–380 (1970).

    Article  CAS  Google Scholar 

  • Swift, C.C.; Homeida, M.; Halliwell, M. and Roberts, C.J.C.: Antipyrine disposition and liver size in the elderly. European Journal of Clinical Pharmacology 14: 149–152 (1978)

    Article  PubMed  CAS  Google Scholar 

  • Traeger, A.; Kunze. H; Stein, G. and Ankermann, H.; Zur Pharmakokinetik von Indometazin bei alten Mänschen. Zeitschrift für Alternforschung 27: 151–155 (1973).

    CAS  Google Scholar 

  • Triggs, E.J.; Nation, R.L.; Long, A. and Ashley, J.J.: Pharmacokinetics in the elderly. European Journal of Clinical Pharmacology 8: 55–62 (1974).

    Article  Google Scholar 

  • Vesell, E.S. and Page, J.G.: Genetic control of dicoumarol levels in man. Journal of Clinical Investigation 47: 2657–2663 (1968)

    Article  PubMed  CAS  Google Scholar 

  • Vesell, E.S. and Page, J.G.: Genetic control of drug levels in man: Antipyrine. Science 161: 72–73 (1975)

    Article  Google Scholar 

  • Vestal, R.E.; Norris, A.H.; Tobin, J.D.; Cohen, B.H.; Shock, N.W. and Andres, R.: Antipyrine metabolism in man: Influence of age, alcohol, caffeine and smoking. Clinical Pharmacology and Therapeutics 18: 425–432 (1975).

    PubMed  CAS  Google Scholar 

  • Wilkinson, G.R.: The effects of ageing on the disposition of benzodiazepines in man; in Crooks and Stevenson (Eds) Drugs and the Elderly, pp 103–116 (Macmillan, London 1979)

    Google Scholar 

  • Wilkinson, G.R. and Shand, D.G.: A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390 (1975)

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Endocrinological Department F and Ultrasonic Laboratory, Herlev University Hospital, Copenhagen, Denmark

    Bodil Bach,  J. Mølholm Hansen, J. P. Kampmann, S. N. Rasmussen & Lis Skovsted

Authors
  1. Bodil Bach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Mølholm Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. P. Kampmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. N. Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lis Skovsted
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bach, B., Hansen, J.M., Kampmann, J.P. et al. Disposition of Antipyrine and Phenytoin Correlated with Age and Liver Volume in Man. Clin Pharmacokinet 6, 389–396 (1981). https://doi.org/10.2165/00003088-198106050-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-198106050-00005

Keywords

Search

Navigation