Population-based modeling to demonstrate extrapancreatic effects of
tolbutamide.
Rostami-Hodjegan, A, Sr Peacey, E George, Sr Heller, and Gt Tucker.
University of Sheffield Department of Medicine and Pharmacology,
The Royal Hallamshire Hospital, Sheffield, S102JF. University
Department of Medicine, Clinical Sciences Centre and Diabetic Centre,
Northern General Hospital, Sheffield, S5 7AU, UK
APStracts 4:0271E, 1997.
Tolbutamide is used increasingly as an investigative tool in in vivo
studies of the physiology of glucose tolerance. Its hypoglycemic
effect in non-diabetic subjects is widely variable reflecting
possible variability in its pharmacokinetics, insulinergic response,
an extrapancreatic effect of the drug or the hypoglycemic effect of
insulin itself. Using population-based modelling, we have
investigated the kinetics and dynamics of tolbutamide and assessed
covariates in two groups of healthy subjects. The results indicate a
high variability in insulinergic effect, measured by the AUC of
insulin (0-60 min) in response to tolbutamide injection (29-96% CV).
However, it appears that impaired insulin sensitivity is compensated
by higher insulin secretion in response to tolbutamide. Thus the
hypoglycemic effect of high insulin secretion is minimal in insulin
resistant subjects. Application of the model indicated that
tolbutamide has appreciable extrapancreatic effects mediated by
prolongation of the residence time of insulin in a remote effect and
by enhancement of glucose effectiveness (GE). An effect in increasing
the insulin sensitivity index (ISI) is also possible but could not be
confirmed statistically for all of the groups of subjects studied.
These observations may explain inconsistencies between the results of
tolbutamide-injection and insulin-injection in the frequently sampled
i.v. glucose tolerance test (FSIGT), and call for further study of
insulin-modified FSIGT vs tolbutamide modified FSIGT in the
assessment of ISI and GEI. (Accepted for the Modeling in Physiology
Section)
Received 26 November 1996; accepted in final form 25 November
1997.
APS Manuscript Number E589-6.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 12 December 1997