Enantioselective Aspects of Drug Action and Disposition: Therapeutic Pitfalls

Jamali, Fakhreddin; Mehvar, Reza; Pasutto, Franco M.

doi:10.1002/jps.2600780902

Cited by 381 publications

(160 citation statements)

References 257 publications

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“…A number of general reviews are available outlining stereoselectivity in both drug action and disposition [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. The purpose of the current paper is to focus on specific pharmacokinetic processes that might be subject to stereoselectivity, providing more recent examples where possible.…”

Section: Introductionmentioning

confidence: 99%

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Brocks

2006

Biopharm. Drug Dispos.

134

108

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Many marketed drugs are chiral and are administered as the racemate, a 50:50 combination of two enantiomers. Pharmacodynamic and pharmacokinetic differences between enantiomers are well documented. Because of enantioselectivity in pharmacokinetics, results of in vitro pharmacodynamic studies involving enantiomers may differ from those in vivo where pharmacokinetic processes will proceed. With respect to pharmacokinetics, disparate plasma concentration vs time curves of enantiomers may result from the pharmacokinetic processes proceeding at different rates for the two enantiomers. At their foundation, pharmacokinetic processes may be enantioselective at the levels of drug absorption, distribution, metabolism and excretion. In some circumstances, one enantiomer can be chemically or biochemically inverted to its antipode in a unidirectional or bidirectional manner. Genetic consideration such as polymorphic drug metabolism and gender, and patient factors such as age, disease state and concomitant drug intake can all play a role in determining the relative plasma concentrations of the enantiomers of a racemic drug. The use of a nonstereoselective assay method for a racemic compound can lead to difficulties in interpretation of data from, for example, bioequivalence or dose/concentration vs effect assessments. In this review data from a number of representative studies involving pharmacokinetics of chiral drugs are presented and discussed.

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Section: Introductionmentioning

confidence: 99%

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Brocks

2006

Biopharm. Drug Dispos.

134

108

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“…Like most arylpropionic acid NSAIDs in clinical use, ximoprofen has an asymmetric centre in the propionate side-chain but is available as the racemate. Some, but not all of these drugs undergo unidirectional stereoselective inversion in the body from the apparently therapeutically inactive R-enantiomer to the corresponding but active S-antipode (Jamali et al, 1989). The existing data suggest that the corresponding R-and S-isomers of ximoprofen are eliminated at similar rates, and consequently, the pharmacokinetics of the racemate reported in this paper can be considered to reflect those of the respective isomers.…”

Section: Introductionmentioning

confidence: 75%

Pharmacokinetics of the anti‐inflammatory drug ximoprofen in healthy young and elderly subjects: comparison with elderly rheumatic patients.

Taylor¹,

Chasseaud²,

Taylor³

et al. 1991

Brit J Clinical Pharma

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The pharmacokinetics of ximoprofen were studied in young and elderly subjects after single and repeated doses up to 30 mg. In healthy elderly subjects (30 mg dose), a mean peak plasma drug concentration of 1.78 micrograms ml‐1 +/‐ 0.83 s.d. occurred at a mean time of 1.95 h +/‐ 1.40 s.d. and, thereafter, concentrations declined monoexponentially with a mean half‐life of 3.8 h +/‐ 1.4 s.d. Comparison of these data with those from younger healthy subjects showed that peak drug concentrations, areas under the curve and half‐lives were about two‐ fold greater in the elderly, these differences probably reflecting a lower systemic drug clearance. Similar results were obtained on comparing data from young healthy subjects and elderly rheumatic patients receiving single and repeated doses of ximoprofen (15 mg twice daily). In patients, the half‐life of ximoprofen was 2.5 h +/‐ 0.7 s.d. Within either group, pharmacokinetic parameters after single or repeated doses were similar: ximoprofen did not accumulate in the plasma of the young or elderly.

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“…Enantiomeric purity analysis of enantiomers online is very important in the process control of pharmaceutical industry due to their different biological activities [1] , while having the same physical and chemical properties [2] . In this work, the UV and CD detectors in series as the online monitoring systems to determine the enantiomer concentration was applied.…”

Section: Introductionmentioning

confidence: 99%

Online Determination of the Enantiomer Concentration Using HPLC Coupled with UV and Circular Dichroism Detectors

Li¹,

Chen²,

Jiang³

2015

Proceedings of the International Conference on Chemical, Material and Food Engineering

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ABSTRACT-The application of ultraviolet absorption detector (UV) and circular dichroism (CD) detectors in series in HPLC systems has been increased in recent years. In this work, an effective method to determine the enantiomer concentration on line in chiral drugs was explored. Ibuprofen (IBP) racemate was applied. The total concentration and concentration difference of S-(+)-IBP and R-(-)-IBP were obtained by the online monitoring systems in HPLC systems. The single enantiomer respective concentrations were also calculated. The UV and CD detectors in series as the online monitoring systems to determine the enantiomer concentration was applied. This method is gradually developed into a practical tool for enantiomeric purity analysis. A new method which can fit the two components respectively rather than both components in the fitting procedure of Inverse method (IM) was provided. This research shows that a commercially available UV and CD detectors in series can be successfully used to determine the enantiomer concentration.

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Enantioselective Aspects of Drug Action and Disposition: Therapeutic Pitfalls

Cited by 381 publications

References 257 publications

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Pharmacokinetics of the anti‐inflammatory drug ximoprofen in healthy young and elderly subjects: comparison with elderly rheumatic patients.

Online Determination of the Enantiomer Concentration Using HPLC Coupled with UV and Circular Dichroism Detectors

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