Summary
The plasma concentration of chlormethiazole and two of its metabolites has been measured in three young and three aged human subjects following administration of a single oral dose of chlormethiazole. A sensitive analytical method based on gas chromatography-mass spectrometry using the selective ion monitoring mode of operation was developed to permit quantitation of the plasma levels. The time course of the plasma concentration of chlormethiazole and metabolites showed wide inter-subject variation, particularly between the young and elderly subjects. Absorption of chlormethiazole was rapid in the subjects of both groups as assessed by the time taken to reach the peak plasma concentration. The mean peak plasma level of chlormethiazole was more than five times greater in the elderly (2.90±1.56 µg/ml) than in the young (0.55±0.58 µg/ml) subjects. The plasma level of chlormethiazole was consistently higher in the aged subjects and this was reflected by the larger area under the plasma curve in aged (7.62±5.37 µg.h/ml) than in young (0.94±0.66 µg.h/ml) individuals. Decreased pre-systemic elimination by the liver has been suggested as an important factor contributing to the higher plasma level in the elderly. Estimates of absolute systemic availability, calculated by reference to previous intravenous studies, were greater for the elderly subjects. The distribution of chlormethiazole in whole blood from six young and six elderly human subjects was investigated in vitro. The unbound fraction of chlormethiazole in plasma increased significantly from 0.308±0.035 in young subjects to 0.403±0.067 in the elderly. Distribution of the drug in whole blood was different for the two age groups; the fraction of drug distributed to plasma water was significantly greater and the fraction in blood cells was significantly less in the aged.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Moore, R. G., Triggs, E. J., Shanks, C. A., Thomas, J.: Pharmacokinetics of chlormethiazole in humans. Europ. J. clin. Pharmacol.8, 353–357 (1975)
Nation, R. L., Learoyd, B., Barber, J., Triggs, E. J.: The pharmacokinetics of chlormethiazole following intravenous administration in the aged. Europ. J. clin. Pharmacol.10, 407–415 (1976)
Lindberg, U. H.: Compounds related to clomethiazole IV. 4-Methylthiazoles and oxazoles with polar side-chains and some other analogues of clomethiazole. Acta pharm. suec.8, 39–48 (1971)
Moore, R. G., Robertson, A. V., Smyth, M. P., Thomas, J., Vine, J.: Metabolism and urinary excretion of chlormethiazole in humans. Xenobiotica5, 687–696 (1975)
Wilkinson, G. R., Shand, D. G.: A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther.18, 377–390 (1975)
Thomas, J., Long, G., Moore, G., Morgan, D.: Plasma protein binding and placental transfer of bupivacaine. Clin. Pharmacol. Ther.19, 426–434 (1976)
Ehrnebo, M., Agurell, S., Boreus, L. O., Gordon, E., Lonroth, U.: Pentazocine binding to blood cells and plasma proteins. Clin. Pharmacol. Ther.16, 424–429 (1974)
Goldstein, A., in: Biostatistics: An Introductory Text, pp. 55–58. New York: MacMillan 1964
Gibaldi, M., Perrier, D., in: Pharmacokinetics, pp. 146–153 (ed. Swarbrick, J.). New York: Marcel Dekker 1975
Rowland, M.: Application of clearance concepts to some literature data on drug metabolism in the isolated perfused liver preparation and in vivo. Europ. J. Pharmacol.17, 352–356 (1972)
Nies, A. S., Shand, D. G., Wilkinson, G. R.: Altered hepatic blood flow and drug disposition. Clin. Pharmacokin.1, 135–155 (1976)
Castleden, C. M., Kaye, C. M., Parsons, R. L.: The effect of age on plasma levels of propranolol and practolol in man. Brit. J. clin. Pharmacol.2, 303–306 (1975)
Bradley, S. E., Ingelfinger, F. J., Bradley, G. P., Curry, J. J.: The estimation of hepatic blood flow in man. J. clin. Invest.24, 890–897 (1945)
Flood, C., Gherondache, C., Pincus, G., Tait, J. F., Tait, S. A. S., Willoughby, S.: The metabolism and secretion of aldosterone in elderly subjects. J. clin. Invest.46, 960–966 (1967)
Sherlock, S., Bearn, A. G., Billing, B. H., Paterson, J. C. S.: Splanchnic blood flow in man by the bromsulfalein method: The relation of peripheral plasma bromsulfalein level to the calculated flow. J. Lab. clin. Med.35, 923–932 (1950)
Bender, A. D., Post, A., Meier, J. P., Higson, J. E., Reichard, G.: Plasma protein binding of drugs as a function of age in adult human subjects. J. Pharm. Sci.64, 1711–1713 (1975)
Woodford-Williams, E., Alvares, A. S., Webster, D., Landless, B., Dixon, M. P.: Serum protein patterns in ‘normal’ and pathological ageing. Gerontologia10, 86–99 (1964)
Hughes, I. E., Ilett, K. F., Jellett, L. B.: The distribution of quinidine in human blood. Brit. J. clin. Pharmacol.2, 521–525 (1975)
Kurata, D., Wilkinson, G. R.: Erythrocyte uptake and plasma binding of diphenylhydantoin. Clin. Pharmacol. Ther.16, 355–362 (1974)
Hughes, I. E., Jellett, L. B., Ilett, K. F.: The influence of various factors on the in vitro distribution of haloperidol in human blood. Brit. J. clin. Pharmacol.3, 285–288 (1976)
Chan, K., Kendall, M. J., Mitchard, M., Wells, W. D. E., Vickers, M. D.: The effect of ageing on plasma pethidine concentration. Brit. J. clin. Pharmacol.2, 297–302 (1975)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nation, R.L., Vine, J., Triggs, E.J. et al. Plasma level of chlormethiazole and two metabolites after oral administration to young and aged human subjects. Eur J Clin Pharmacol 12, 137–145 (1977). https://doi.org/10.1007/BF00645135
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00645135