Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination

Lees, P.; Hunter, R. P.; Reeves, Phil; Toutain, Pierre‐Louis

doi:10.1111/j.1365-2885.2012.01367.x

Cited by 20 publications

(12 citation statements)

References 55 publications

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“…Another likely contributing process accounting for the differences between enantiomers in C max and AUC is first-pass metabolism [21]. As first-pass metabolism is an enzymatic process, it exhibits molecular recognition at saturable binding sites and would also give rise to interference between the enantiomers.…”

Section: Stereoisomer-mediated Pharmacokinetics Arising From First-pamentioning

confidence: 99%

“…Indeed, inclusion of an inactive enantiomer provides nothing but an impurity or 'isomeric ballast, as coined by Ariens [16,20]. The resulting concern was stated by Lees et al [21]: "An impurity at the level 50% of the active constituent would never be tolerated by regulatory authorities for any other constituent, which is neither an active, nor excipient nor solvent. ".…”

Section: Introductionmentioning

confidence: 99%

“…Chirality affects not only the pharmacodynamic properties of potency, efficacy and affinity, it also affects pharmacokinetic processes of absorption, distribution, metabolism and excretion [21,22]. Accordingly, both the US Food and Drug Administration's Guidance for Industry on Funding: This study was financially supported by IntraBio (https://intrabio.com).…”

Section: Introductionmentioning

confidence: 99%

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Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

et al. 2020

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The enantiomers of many chiral drugs not only exhibit different pharmacological effects in regard to targets that dictate therapeutic and toxic effects, but are also handled differently in the body due to pharmacokinetic effects. We investigated the pharmacokinetics of the enantiomers of N-acetyl-leucine after administration of the racemate (N-acetyl-DL-leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-leucine). The results suggest that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. Compounds were administered orally to mice. Plasma and tissue samples were collected at predetermined time points (0.25 to 8 h), quantified with liquid chromatography/mass spectrometry, and pharmacokinetic constants were calculated using a noncompartmental model. When administered as the racemate, both the maximum plasma concentration (C max) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer. When administered as the L-enantiomer, the dose proportionality was greater than unity compared to the racemate, suggesting saturable processes affecting uptake and/or metabolism. Elimination (k e and T 1/2) was similar for both enantiomers. These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation. In brain and muscle, N-acetyl-L-leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-leucine and utilization by normal leucine metabolism. In summary, the enantiomers of N-acetyl-leucine exhibit large, unexpected differences in pharmacokinetics due to both unique handling and/or inhibition of uptake and metabolism of the Lenantiomer by the D-enantiomer. Taken together, these results have clinical implications supporting the use of N-acetyl-L-leucine instead of the racemate or N-acetyl-D-leucine, and support the research and development of only N-acetyl-L-leucine.

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Section: Stereoisomer-mediated Pharmacokinetics Arising From First-pamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

et al. 2020

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“…Potency has been defined as the amount of a drug required to produce an effect of a given intensity and the ‘potency ratio’ in vivo as the ratio of the doses producing effects of the same intensity (Lees et al. ). Research from rats, mice and humans suggest a potency ratio of 1:2 between racemic ketamine and S‐ketamine, while an experimental study in dogs indicated that the mean ratio of potency might be lower (1:1.29) in this species (Duque et al.…”

Section: Introductionmentioning

confidence: 99%

S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents

Casoni

Spadavecchia

Adami

2015

Veterinary Anaesthesia and Analgesia

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“…Indeed, many studies have demonstrated that stereoisomers of a chiral drug often exhibited pronounced differences in their pharmacokinetic and metabolic profiles both quantitatively and qualitatively [16,123]. In addition to differences in potency and other pharmacodynamic properties, most members of enantiomeric pairs commonly differ also in their pharmacokinetic profiles [124,125]. A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic proton-pump inhibitors.…”

Section: Pharmacokinetic Differences Between Enantiomersmentioning

confidence: 99%

Exploiting the Power of Stereochemistry in Drugs: An Overview of Racemic and Enantiopure Drugs

Sekhon¹

2013

J. Mod. Med. Chem.

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Stereochemistry is one of the essential dimensions in pharmacology as it dictates how enantiomers interact with biological systems. Chirality is very important in drug design. Enantiomers of the same chiral drug can have different pharmacodynamic and/or pharmacokinetic properties. In this context, replacing some existing racemates with single isomers has resulted in improved safety and/or efficacy profile of various racemates. Single enantiomer drug use can potentially lead to simpler and more selective pharmacologic profiles, improved therapeutic indices, simpler pharmacokinetics due to different rates of metabolism of the different enantiomers, decreased drug interactions, and drug companies are increasingly using chiral switching as a marketing strategy. Additionally, due to different pharmacological activity, enantiomers of chiral drugs can differ in toxicity. However, unpredicted toxicity has been reported in some chiral switching cases which has resulted the withdrawal of the enantiomer from the market or a halt in its development. In view of above, before switching to single enantiomer drugs, prescribers should look for evidence from well-conducted clinical trials to prove that the chiral switch is cost-effective and improves the outcomes for patients rather than patents. The U.S. Food and Drug Administration (FDA) have allowed single enantiomers of generic drugs to be patented and marketed under different name. FDA regulations require that all chiral bioactive drug molecules must be isolated and tested for the efficacy and safety, and have to be as pure as possible containing a single pure enantiomer.

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Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination

Cited by 20 publications

References 55 publications

Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents

Exploiting the Power of Stereochemistry in Drugs: An Overview of Racemic and Enantiopure Drugs

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