The Relationship Between the Pharmacokinetics and Pharmacodynamic Effects of Oral Hypoglycaemic Drugs

Abstract

Oral hypoglycaemic drugs have widely differing pharmacokinetic properties. Possible pharmacodynamic benefits include greater efficacy and fewer adverse effects. In general, it has not been possible to demonstrate unequivocal differences in clinical efficacy between the sulphonylureas during long term use, although there are clear differences in potency. These differences have been emphasised to the extent that the term 'second-generation' has been used for the most potent sulphonylureas, but there is little to suggest that potency is of any therapeutic significance. Trials to study differences in efficacy have rarely been of acceptable design. They have often used fixed doses of drugs, begging the question of whether true potency ratios have been established for chronic treatment. They have rarely involved substantial numbers of patients in double-blind crossover studies with a suitable washout period. Trials which show that there is a clear relationship between drug concentrations in blood and drug effects (whether therapeutic effects or adverse effects such as severe hypoglycaemia) are generally lacking. Qualitative and semiquantitative analysis of adverse effects supports the concept that drugs with a long half-life (e.g. chlorpropamide), renally excreted active metabolites (e.g. acetohexamide) or unusual properties (e.g. glibenclamide, which accumulates progressively in islet tissue) are more likely to cause prolonged hypoglycaemia, which may be fatal. The major adverse effect of treatment with biguanides is lactic acidosis, and this probably occurs more commonly in patients treated with phenformin than those treated with metformin because of pharmacogenetic variation in phenformin metabolism. The available evidence therefore favours the use of drugs with a short elimination half-life which are extensively metabolised and which have no active metabolites.

The effect of cholestyramine and activated charcoal on glipizide absorption.

“…It has been suggested that glipizide undergoes enterohepatic circulation (Ferner & Chaplin, 1987). If this were the case, the presence of charcoal or cholestyramine in the gastrointestinal tract might enhance the elimination of glipizide by interrupting the enterohepatic circulation.…”

Glibenclamide-pregnenolone derivative has greater hypoglycemic effects and biodistribution than glibenclamide-OH in alloxan-rats

“…Nevertheless, there are reports that glibenclamide can induce hypoglycemia, even at low doses, especially in the elderly 7,8 . In addition, drug interactions and renal dysfunction are suspected to contribute to hypoglycemic episodes but little is known about their effect on glibenclamide pharmacokinetics 9,10 and information on the characteristics of its dose-response relationship is not clear.…”

Pharmacokinetic and pharmacodynamic studies of glibenclamide in non‐ insulin dependent diabetes mellitus.

“…Drug interactions (Feldman, 1985). Many aspects of its clinical and impaired renal function are suspected to Correspondence: Professor A. F. Lant, Department of Clinical Pharmacology and Therapeutics, Westminster Hospital, London SWIP 2AP contribute to hypoglycaemic episodes, but little is known about their effect on glibenclamide pharmacokinetics (Asplund et al, 1983;Ferner & Chaplin, 1987;Pearson et al, 1986). These problems and the lack of understanding of the dose-response relationship for the drug (Nattrass, 1986;Wahlin-Boll et al, 1982), complicate the clinical use of the drug.…”

“…The apparent lack of consistency in the pharmacokinetics of glibenclamide, coupled with the incomplete information on the characteristics of its dose-response relationship (Ferner & Chaplin, 1987;Marchetti & Navalesi, 1989;Nattrass, 1986), often makes it difficult to determine optimum drug dosage in the individual diabetic patient. Some of the reported inconsistencies reflect the fact that kinetic profiles for the drug have been determined in animals or healthy volunteers rather than in diabetic patients (Adams et al, 1982;Ings et al, 1981).…”