Absorption kinetics of oral sotalol combined with cisapride and sublingual sotalol in healthy subjects

Deneer,; Lie-A-Huen,; Kingma,; Proost,; Kelder,; Brouwers,

doi:10.1046/j.1365-2125.1998.00706.x

Cited by 7 publications

(1 citation statement)

References 27 publications

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“…While evidence for carrier-mediated transport, mainly by hPEPT1, exists for a majority of these drugs, and hence the Caco-2 system is obviously not the optimal experimental method, the case of the β-blocker sotalol, with no evidence for carrier-mediated transport, represents a valid challenge to the BCS classification approach. Based on plasma levels following oral vs intravenous administration, the oral absorption of sotalol in humans has been shown to be nearly complete. − However, transepithelial transport studies across Caco-2 cell monolayers revealed low permeability for sotalol. − …”

Section: Introductionmentioning

confidence: 99%

High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations

et al. 2010

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The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F(abs)) in humans is 90% or higher. This direct correlation between human permeability and F(abs) has been recently controversial, since the β-blocker sotalol showed high F(abs) (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F(abs). The effective permeabilities (P(eff)) of sotalol and metoprolol, a FDA standard for the low/high P(eff) class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P(eff) at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol's at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK(a) and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol-buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolol's P(eff) value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalol's permeability is low at pH 6.5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high F(abs). In conclusion, we have shown that, in fact, there is no discrepancy between P(eff) and F(abs) in sotalol's absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.

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Section: Introductionmentioning

confidence: 99%

High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations

et al. 2010

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Biopharmaceutical Modeling for Miscellaneous Cases

Sugano

2012

Biopharmaceutics Modeling and Simulations

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Absorption kinetics and pharmacodynamics of two oral dosage forms of flecainide in patients with an episode of paroxysmal atrial fibrillation

Deneer

Lie‐A‐Huen

Kingma

et al. 2004

Eur J Clin Pharmacol

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The probability of cardioversion after an oral loading dose of flecainide in patients with AF is dependent on ka. Rapid loading of the effect compartment, i.e. the atria, appears to be critical to reach cardioversion. Higher flecainide serum concentrations and a more rapid absorption does not increase interindividual variability of pharmacokinetics and pharmacodynamics, which is important when safety is considered.

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Absorption kinetics of oral sotalol combined with cisapride and sublingual sotalol in healthy subjects

Cited by 7 publications

References 27 publications

High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations

High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations

Biopharmaceutical Modeling for Miscellaneous Cases

Absorption kinetics and pharmacodynamics of two oral dosage forms of flecainide in patients with an episode of paroxysmal atrial fibrillation

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