Stereoselective and isozyme‐selective drug interactions

Abstract

A surprisingly large number of marketed drugs are racemic mixtures. The pharmacokinetic literature on racemic drugs contains a vast amount of information on drug-drug interactions derived from the measurement of total drug concentrations in plasma and urine. The appreciation of the role of stereochemistry in drug interactions with racemic warfarin resulted in a long-overdue scientific rigor being applied to the study of drug interactions. It also compelled us to recognize that much of the literature was uninterpretable. A better understanding of oxidative metabolism, particularly the complexity of the cytochrome P-450 family of enzymes, has also strengthened the scientific basis of drug interactions. We now recognize that investigators and clinicians must consider both stereoselectivity and isozyme selectivity in the study of drug interactions to understand the nature of the interaction so as to more effectively use new and potent drugs.

Stereoselectivity in drug metabolism

“…Two enantiomers in the racemic mixture may not be passive components, and may interact with one another, resulting in enantiomeric interaction due to the competition for the same metabolic pathway(s) that are mediated by the same enzyme(s) [47]. Stereoselective pharmacokinetics of ifosfamide was observed in the rat model [22,23] (S)-ifosfamide were significantly increased with nonrenal clearance being decreased following the intravenous administration of racemate compared with those observed after the administration of individual enantiomers [23].…”

“…The alteration in the activity of enzymes responsible for metabolism of chiral drugs can affect stereoselectivity in pharmacokinetics, and hence factors modulating the activity of metabolic enzymes can change the pharmacologic effect [47][48][49]. The same enzyme(s) can mediate the biotransformation of two enantiomers of a chiral drug at different rates so that both enantiomers can potentially interact and be mutually inhibitory, resulting in an enantiomeric interaction.…”

“…The other scenario is that different enzymes are responsible for the metabolism of the enantiomers of a chiral drug (e.g., warfarin). The selective induction or inhibition of enzyme(s) by coadministered drugs will alter the stereoselectivity in drug disposition of the chiral drug [47,49].…”

Regiospecific and Stereospecific Triangulation of the Structures of Metabolites Formed by Sequential Metabolism at Multiple Prochiral Centers

“…This topic has been the subject of periodic review (Jenner and Testa, 1973;Eichelbaum, 1988;Waxman, 1988;Trager 1989;Gibaldi 1993;Oguri et al, 1994;Caldwell 1995;Brocks, 2006;Lu, 2007;Campo et al, 2009). Chirality can be introduced to a single enantiomer drug by a metabolic or chemical racemization, or to an achiral drug by metabolism at a prochiral (enantiotopic) center.…”

The Impact of Stereoisomerism in Bioequivalence Studies

“…[1][2][3][4][5][6][7][8][9][10][11][12] The impact of stereoisomerism in bioequivalence (BE) studies, however, remains an issue of controversy. [13][14][15][16][17][18][19][20][21] Those in favor of the use of stereoselective methods in BE studies tend to build their case on theoretical pharmacokinetic, pharmacodynamic, or toxicological grounds and on the fact that stereoselective analytical methods are now available for many chiral drugs.…”