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The area of Drug Discovery has undergone an amazing evolution in the past decade. This evolution is typified by the development of automated combinatorial synthesis and high throughput pharmacological testing. This, in turn, has lead to the ability to create and mine extensive databases and then model this new information. The overall result is a substantial increase in the rate of target identification, generation of new leads, and finally, optimization of those leads into clinical candidates. ADME studies have always played a critical role in helping to optimize the pharmacokinetic (PK) properties of new drugs thereby increasing their success rate. As a consequence of the increased throughput of drug discovery, ADME studies have evolved to keep pace. These so-called “early ADME” studies, are characterized by parallel processing and higher throughput than before. A primary concern of medicinal chemists is to design molecules that will have not only the desired activity, but also suitable potency and duration of action, which is influenced by pharmacokinetic properties such as bioavailability and half-life. This article focuses on a particular subset of eADME studies known as “metabolic stability”, which can be an important contributor for a good pharmacokinetic profile. Metabolic stability studies represent the adaptation of more complex metabolism rate studies to a minimized system suitable for parallel processing of large numbers of compounds. The theoretical basis for metabolic stability lies in its relationship to the concept of metabolic intrinsic clearance. Typical metabolic stability protocols are discussed with respect to their relation to drug design. How metabolic stability studies have evolved to keep pace with advances in drug discovery is also discussed.Several case studies of the role of metabolic stability in drug design over the past few years are summarized to exemplify the utility of this kind of study. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.

The mass balance of 14C bismuth sucrose octasulfate (BISOS) was investigated in eight male Sprague–Dawley rats after single oral doses of 1·0 g kg−1. Bismuth and radioactivity were monitored in blood, urine, and feces for up to 144 h post‐dose, while kidneys, brain, liver, and lungs were assayed for bismuth at 144 h post‐dose. In a separate experiment, bismuth was monitored in bile of bile‐duct‐cannulated animals for 48 h post‐dose. Fecal excretion of bismuth averaged 95·8±5·30% bismuth dose, while 99·2±3·63% of the radiolabel was excreted in feces. Urinary excretion of bismuth averaged 0·051±0·028% bismuth dose, and 1·83±1·08% radioactive dose. Biliary excretion of bismuth averaged 0·0003±0·0006% bismuth dose, and 0·026±0·030% radiolabeled dose. An average 0·005±0·002% of the bismuth dose was present in kidney, liver, and lung. Bismuth levels in brain were below quantifiable limits. Though BISOS contains 57·3% by weight of bismuth, peak blood concentrations of bismuth were three orders of magnitude lower than for BISOS equivalents (Cmaxfor BISOS averaged 110±55·4 μg eq mL−1, while for bismuth it was 26·1±10·3 ng mL−1). This data indicates that bismuth dissociates from sucrose octasulfate, probably during the absorption phase, and exhibits differential pharmacokinetic characteristics from sucrose octasulfate. The low biliary and urinary excretion of both bismuth and BISOS equivalents is indicative of low systemic absorption. Greater than 96% recovery in feces, bile, and urine indicates that mass balance was achieved following oral administration. © 1997 John Wiley & Sons, Ltd.

The mass balance of ¹⁴C bismuth sucrose octasulfate (BISOS) was investigated in eight male Sprague–Dawley rats after single oral doses of 1·0 g kg⁻¹. Bismuth and radioactivity were monitored in blood, urine, and feces for up to 144 h post-dose, while kidneys, brain, liver, and lungs were assayed for bismuth at 144 h post-dose. In a separate experiment, bismuth was monitored in bile of bile-duct-cannulated animals for 48 h post-dose. Fecal excretion of bismuth averaged 95·8±5·30% bismuth dose, while 99·2±3·63% of the radiolabel was excreted in feces. Urinary excretion of bismuth averaged 0·051±0·028% bismuth dose, and 1·83±1·08% radioactive dose. Biliary excretion of bismuth averaged 0·0003±0·0006% bismuth dose, and 0·026±0·030% radiolabeled dose. An average 0·005±0·002% of the bismuth dose was present in kidney, liver, and lung. Bismuth levels in brain were below quantifiable limits. Though BISOS contains 57·3% by weight of bismuth, peak blood concentrations of bismuth were three orders of magnitude lower than for BISOS equivalents (Cmax for BISOS averaged 110±55·4 μg eq mL⁻¹, while for bismuth it was 26·1±10·3 ng mL⁻¹). This data indicates that bismuth dissociates from sucrose octasulfate, probably during the absorption phase, and exhibits differential pharmacokinetic characteristics from sucrose octasulfate. The low biliary and urinary excretion of both bismuth and BISOS equivalents is indicative of low systemic absorption. Greater than 96% recovery in feces, bile, and urine indicates that mass balance was achieved following oral administration. © 1997 John Wiley & Sons, Ltd.