The pharmacokinetics and pharmacodynamics of quinidine and 3‐ hydroxyquinidine.

Wooding-Scott, Ronald A.; Smalley, James; Visco, John P.; Slaughter, Richard L.

doi:10.1111/j.1365-2125.1988.tb03400.x

Cited by 14 publications

(9 citation statements)

References 18 publications

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“…For multi-MPS platform II they were: betaxolol 37 , linezolid 38 , pindolol 39 , prednisolone 40 , quinidine 41 , ranitidine 42 , theophylline 43 and timolol 44 .…”

Section: Methodsmentioning

confidence: 99%

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Maaß

Stokes²,

Griffith

et al. 2017

Integr. Biol.

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Microphysiological systems (MPS) provide relevant physiological environments in vitro for studies of pharmacokinetics, pharmacodynamics and biological mechanisms for translational research. Designing multi-MPS platforms is essential to study multi-organ systems. Typical design approaches, including direct and allometric scaling, scale each MPS individually and are based on relative sizes not function. This study’s aim was to develop a new multi-functional scaling approach for integrated multi-MPS platform design for specific applications. We developed an optimization approach using mechanistic modeling and specification of an objective that considered multiple MPS functions, e.g., drug absorption and metabolism, simultaneously to identify system design parameters. This approach informed the design of two hypothetical multi-MPS platforms consisting of gut and liver (multi-MPS platform I) and gut, liver and kidney (multi-MPS platform II) to recapitulate in vivo drug exposures in vitro. This allows establishment of clinically relevant drug exposure-response relationships, a prerequisite for efficacy and toxicology assessment. Design parameters resulting from multi-functional scaling were compared to designs based on direct and allometric scaling. Human plasma time-concentration profiles of eight drugs were used to inform the designs, and profiles of an additional five drugs were calculated to test the designed platforms on an independent set. Multi-functional scaling yielded exposure times in good agreement with in vivo data, while direct and allometric scaling approaches resulted in short exposure durations. Multi-functional scaling allows appropriate scaling from in vivo to in vitro of multi-MPS platforms, and in the cases studied provides designs that better mimic in vivo exposures than standard MPS scaling methods.

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“…For multi-MPS platform II they were: betaxolol 37 , linezolid 38 , pindolol 39 , prednisolone 40 , quinidine 41 , ranitidine 42 , theophylline 43 and timolol 44 .…”

Section: Methodsmentioning

confidence: 99%

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Maaß

Stokes²,

Griffith

et al. 2017

Integr. Biol.

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“…The final structures of the local energy minima are shown in Fig. 4. The (Dl and 0 3 torsional angles of these six conformations, along with those found in the X-ray crystallographic structures of Fig.…”

mentioning

confidence: 88%

(3S)-3-hydroxyquinidine, the major biotransformation product of quinidine. Synthesis and conformational studies. X-Ray molecular structure of (3S)-3-hydroxyquinidine methanesuiphonate

Carroll¹,

Abraham²,

Gaetano³

et al. 1991

J. Chem. Soc., Perkin Trans. 1

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Hydroxyquinidine, the major metabolite of the Cinchona alkaloid quinidine, vvas prepared by synthetic chemical modification or microbial oxidation of quinidine. The structure of this metabolite has been demonstrated to be (3S)-3-hydroxyquinidine by 'H and 13C NMR, IR, UV and mass spectral analysis. Previously published comparisons of the 13C N M R spectra of 3-hydroxyquinidine and model compounds were used to establish the absolute stereochemistry of the metabolite (see ref. 8). This assignment has been verified by single-crystal X-ray analysis of ( 3 s ) -3hydroxyquinidine methanesulphonate. The gas-and solution-phase conformational preference of the metabolite derived from molecular modelling and NOE studies are compared with the conformation observed by X-ray crystallography.

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“…57). Following oral quinidine administration, concentrations of the metabolite are not as great as quinidine; however, it has lower plasma protein binding and thus the free concentrations of quinidine and 3-hydroxyquinidine are about the same (Wooding-Scott et al, 1988). 3-Hydroxyquinidine has been administered to humans directly, with measurement of cardiac pharmacodynamic endpoints (Vozeh et al, 1985), which is an excellent way to gather data that can be used in estimating the contribution of the metabolite to the parent drug action.…”

mentioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

138

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The pharmacokinetics and pharmacodynamics of quinidine and 3‐ hydroxyquinidine.

Cited by 14 publications

References 18 publications

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

(3S)-3-hydroxyquinidine, the major biotransformation product of quinidine. Synthesis and conformational studies. X-Ray molecular structure of (3S)-3-hydroxyquinidine methanesuiphonate

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

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