Relative bioavailability of two disopyramide capsules in humans based on total, unbound, and unbound enantiomer concentrations

Takahashi, Harumi; Ogata, Hiroyasu; Shimizu, Mikiko; Hashimoto, Kayoko; Masuhara, Keiso; Kashiwada, Kazuko; Someya, Kazuhiko

doi:10.1002/bdd.2510140507

Cited by 3 publications

(3 citation statements)

References 17 publications

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“…Numerous studies have demonstrated differences in the dissolution and absorption of crystalline forms of the racemate vs. the individual enantiomers (e.g., ketoprofen [12], disopyramide [13], lansoprazole [14], verapamil [15], tramadol [16], anesthetic drugs [17], and ibuprofen [18]). Drug absorption from the gastrointestinal (GI) tract is largely passive and mediated by drug solubility and permeability; blood levels [e.g., the area under the curve (AUC)] are also generally a reflection of the dose administered or concentration released over time.…”

Section: Supercritical Fluid Chromatography (Sfc)mentioning

confidence: 99%

Regulatory and Development Considerations of Chiral Compounds

Zeid¹

2010

Chiral Separation Methods for Pharmaceutical and Biotechnological Products

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OVERVIEWThe importance of chirality in biological systems has been well recognized for over 50 years, due largely to its observed pervasiveness in nature. Although it may be self-evident that chirality plays a critical role in biological activity, it was not until the 1980s that its importance in drug development was recognized. With the advent of improved assay sensitivity and separation techniques of the day, Ariens et al. correctly identified racemic mixtures as fixed-dose combinations of a eutomer, or desired enantiomer, and distomer, or biologically inactive and/or toxic enantiomer [1]. Since then, the universe of chiral science has been expanding at an astonishing rate, with significant developments in analytical methods, the discovery of new stereoselective catalyzing agents, improved manufacturing and separation process controls, and in vitro characterization as evidenced by a larger pool of patents and intellectual property litigation in this area.Although regulatory policies for chiral drug development were put in place nearly 20 years ago, the timing for when to implement these tests in the development plan has not been well defined. Regulatory and development considerations have grown significantly more complicated and layered since then and appear to have resulted in an ad hoc approach instead of a highly integrated program. The focus of this chapter is to provide a more holistic project development plan based on the combined current regulatory guidance and industry experience for the development of racemic drugs and selective enantiomers.

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Section: Supercritical Fluid Chromatography (Sfc)mentioning

confidence: 99%

Regulatory and Development Considerations of Chiral Compounds

Zeid¹

2010

Chiral Separation Methods for Pharmaceutical and Biotechnological Products

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“…Disopyramide is a type Ia anti-arrhythmic agent used clinically for the treatment and prophylaxis of supraventricular and ventricular arrhythmias. Disopyramide has a relatively narrow therapeutic plasma concentration range (2-5 µg mL − 1 ) and shows concentration-dependent binding to plasma proteins in man (Hasselstrom et al 1991 ;Takahashi et al 1991bTakahashi et al , 1993a.…”

Section: Introductionmentioning

confidence: 99%

“…Although disopyramide is available commercially as a racemic mixture, the pharmacokinetic properties of each enantiomer have been reported to be different in man and animals (Cook et al 1982 ;Lima et al 1985 ;Giacomini et al 1986 ;Takahashi et al 1993a ;Masuhara et al 1995). Plasma protein binding of (S )disopyramide is higher than that of (R)-disopyramide in man, and the total clearance of unbound (S )-disopyramide is also higher than that of (R)-disopyramide (Lima et al 1985 ;Takahashi et al 1991a).…”

Section: Introductionmentioning

confidence: 99%

Stereoselective pharmacokinetics and pharmacodynamics of disopyramide and its metabolite in rabbits

Horikawa

Yasumuro

Kanno

et al. 2001

Journal of Pharmacy and Pharmacology

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The extent to which interactions between enantiomers of disopyramide and between disopyramide and its metabolite, mono-N-dealkylated disopyramide (MND), contribute to stereoselectivity of the anti-arrhythmic effect has been investigated in rabbits by measuring the prolongation of the QUc interval. The plasma unbound fraction of disopyramide enantiomers was constant at a concentration range of 1.44-28.9 microM. An intravenous infusion study of the disopyramide enantiomer or racemate suggested that the S-enantiomer had a pharmacological effect, determined by linear regression analysis, approximately 3.3-times more potent than that of the R-enantiomer. Furthermore, the effect caused by racemic disopyramide was the sum of that elicited by both enantiomers individually. No significant difference was observed between the slope of linear regression analysis of intravenous infusion and that of intravenous bolus injection. Single intravenous bolus injection of MND did not affect the QUc intervals. In conclusion, the S-enantiomer of disopyramide was approximately 3.3-times more potent pharmacologically than the R-enantiomer. The relationship between plasma concentration of the disopyramide enantiomers and pharmacological effect was the sum of each enantiomer individually.

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Bioequivalence of Chiral Drugs

Mehvar

Jamali

1997

Clinical Pharmacokinetics

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Guidelines for bioequivalence of non-racemic pharmaceuticals are abundant in the literature. However, few guidelines exist for the bioequivalence of racemic drugs which consist of 2 or more stereoisomers. The aim of this article is to address the question of whether the bioequivalence of racemic drugs should be based on the measurement of the individual enantiomers or that of the total drug. Several pharmacokinetic-pharmacodynamic cases are examined to test the validity of extrapolating the bioequivalence of racemic drugs to that of their individual enantiomers after administration of the racemate; simulation and experimental data are presented to support these cases. It is shown that for drugs which exhibit non-linear pharmacokinetics, the results of bioequivalence studies based on the total drug may differ from those based on the individual enantiomers. Similar discrepancies can be shown for a racemic drug with linear pharmacokinetics whose enantiomers substantially differ from each other in their pharmacokinetic parameters. Therefore, it is suggested that stereospecific assays be used for these drugs. Additionally, it is recommended that for racemic drugs which undergo chiral inversion, and for most products with modified release characteristics, the bioequivalence be assessed using stereospecific assays. Conversely, for racemic drugs with linear pharmacokinetics and minimal to modest stereoselectivity in their kinetic parameters, and for those with non-stereoselective pharmacodynamics, the use of stereospecific analytical methods are not warranted. Finally, the limited, controversial literature in favour of or against the use of stereospecific assays in bioequivalence of chiral drugs are reviewed and a preliminary guideline is proposed.

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Relative bioavailability of two disopyramide capsules in humans based on total, unbound, and unbound enantiomer concentrations

Cited by 3 publications

References 17 publications

Regulatory and Development Considerations of Chiral Compounds

Regulatory and Development Considerations of Chiral Compounds

Stereoselective pharmacokinetics and pharmacodynamics of disopyramide and its metabolite in rabbits

Bioequivalence of Chiral Drugs

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