Determination of Rate Constants for In Vitro Three-Compartment Transfer Using a Two-Phase System

Yunker, Martin H.; Borodkin, Saul

doi:10.1002/jps.2600600108

Cited by 13 publications

(3 citation statements)

References 5 publications

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“…Due to rotation of the dialysis cell the oil phase is effectively dispersed in the aqueous buffer in the donor compartment thus creating a large interface between the oil and the aqueous phase. The net rate of drug transfer from the oil phase into the aqueous donor phase is governed by the solute distribution coefficient between the two respective phases and the interfacial area (Yunker and Borodkin 1971;Larsen, Fredholt, and Larsen 2001). Under the conditions employed we therefore assumed that equilibrium between the immiscible phases at any time is established instantaneously (Larsen et al 2006).…”

Section: Tablementioning

confidence: 99%

In Vitro Assessment of Lidocaine Release from Aqueous and Oil Solutions and from Preformed and in Situ Formed Aqueous and Oil Suspensions. Parenteral Depots for Intra-Articular Administration

Pedersen¹,

Larsen²,

Østergaard³

et al. 2008

Drug Delivery

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Section: Tablementioning

confidence: 99%

In Vitro Assessment of Lidocaine Release from Aqueous and Oil Solutions and from Preformed and in Situ Formed Aqueous and Oil Suspensions. Parenteral Depots for Intra-Articular Administration

Pedersen¹,

Larsen²,

Østergaard³

et al. 2008

Drug Delivery

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“…Erythromycin contains a dimethylamino group on the desosamine sugar and has a PKa of 8.6 to 8.9 in H20 (18,21); thus, at physiological pH it exists in both protonated (>96 to 98%) and neutral (2 to <4%) forms. Since reactant concentrations are key terms in the analysis of reaction kinetic constants, it is difficult to evaluate data from the literature without first knowing the relative roles of the neutral and protonated forms of macrolide in binding to bacterial ribosomes.…”

mentioning

confidence: 99%

Role of protonated and neutral forms of macrolides in binding to ribosomes from gram-positive and gram-negative bacteria

Goldman

Fesik

Doran

1990

Antimicrob Agents Chemother

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Erythromycin binds to a single site on the bacterial 50S ribosomal subunit and perturbs protein synthesis. However, erythromycin contains desosamine and thus exists in both protonated (>96%) and neutral (<4%) forms at physiological pH because of the pKa of the dimethylamino group. We therefore examined the relative roles of both forms in binding to ribosomes isolated from two species each of gram-positive and gram-negative bacteria. We developed a system to directly measure the forward (association) rate constant of formation of the macrolide-ribosome complex, and we have measured both the forward and reverse (dissociation) rate constants as a function of pH. Forward rate constants and binding affinity did not correlate with pH when the interaction of erythromycin with ribosomes from both gram-positive and gram-negative bacteria was examined, demonstrating that the protonated form of this macrolide binds to ribosomes. Conversely, the neutral form of macrolide cannot be the sole binding species and appears to bind with the same kinetics as the protonated form.Forward rate constants were 3-to 4-fold greater at physiological pH, and binding affinity calculated from rate constants was 5-to 10-fold greater than previously estimated. Similar results were obtained with azithromycin, a novel 15-membered macrolide that contains an additional tertiary amine in the macrolide ring. Ribosomeand macrolide-specific kinetic parameters were demonstrated at neutral pH and may be related to the potency of the two macrolides against gram-positive and gram-negative bacteria.Erythromycin has been studied and used for antibacterial chemotherapy for over 30 years. Initial efforts were directed towards determination of its mode of action and efficacy in clearing bacterial infections. These early investigations showed that erythromycin was a very safe and effective agent for treating infection due to susceptible bacteria and that its mode of action involved binding to bacterial 50S ribosomal subunits (11, 13) with resultant perturbation of protein synthesis (1, 12). Although the details regarding perturbation of ribosome function are still not entirely understood, binding to a single site on the 50S ribosomal subunit has been firmly established by independent analysis (7-10, 13, 20).Once the existence of the binding site on the 50S subunit was demonstrated, studies shifted to a more detailed evaluation of the kinetic parameters involved. Initial determinations of dissociation constants for the erythromycin-ribosome complex ranged from 10-6 to 10-8 M (3, 4, 10, 13, 16, 20), and the specific dissociation (reverse) rate constant of the [14C]erythromycin-Escherichia coli ribosome complex was 0.15 min-' (16). The study that found the latter result gave only a calculated association (forward) rate constant, 1.5 x 107 liters mol-1 min-', because the forward rate was too fast to be measured under the experimental conditions used. The measured forward rate constants were 1.25 x 105 and 1.36 x 106 liters mol-1 min-' for 50S subunits and 70S ribo...

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“…Mitemcinal has a cationic nature, containing an isopropyl methylamino group on the desosamine sugar (Figure 1), with expected pKa values around 9 according to data on erythromycin (Sabath et al 1968;Yunker and Borodkin 1971). To clarify whether the absorption and the secretion of mitemcinal was affected by the microclimate pH, we also examined the effect of apical pH on mitemcinal transport in Caco-2 monolayers.…”

Section: Discussionmentioning

confidence: 98%

Nonlinear intestinal pharmacokinetics of mitemcinal, the first acid-resistant non-peptide motilin receptor agonist, in rats

et al. 2007

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The objective was to investigate the mechanism of nonlinear pharmacokinetics of mitemcinal, the first acid-resistant non-peptide motilin agonist, in rats. Super-proportional increases of the cumulative rates of radioactivity excreted into bile and urine following oral administration of [3H]-mitemcinal suggested nonlinear absorption of mitemcinal in rats. To evaluate the fraction dose absorbed (Fa) and intestinal availability (Fg), [3H]-mitemcinal was orally administrated to rats, and tritium radioactivity and unchanged mitemcinal concentration were determined in the portal blood. Fa values for 0.2 mg/kg1, 0.5 mg/kg, and 5.0 mg/kg dose groups were 0.314, 0.353, and 0.569, respectively. Corresponding Fg values were 0.243, 0.296, and 0.513, respectively. In Caco-2 experiments, the permeation of [3H]-mitemcinal in the secretory direction was larger than in the absorptive direction and was inhibited by P-glycoprotein (P-gp) substrate digoxin. The results indicate that the saturation of P-gp-mediated membrane permeation and intestinal metabolism causes the nonlinear pharmacokinetics of mitemcinal in rats.

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Determination of Rate Constants for In Vitro Three-Compartment Transfer Using a Two-Phase System

Cited by 13 publications

References 5 publications

In Vitro Assessment of Lidocaine Release from Aqueous and Oil Solutions and from Preformed and in Situ Formed Aqueous and Oil Suspensions. Parenteral Depots for Intra-Articular Administration

In Vitro Assessment of Lidocaine Release from Aqueous and Oil Solutions and from Preformed and in Situ Formed Aqueous and Oil Suspensions. Parenteral Depots for Intra-Articular Administration

Role of protonated and neutral forms of macrolides in binding to ribosomes from gram-positive and gram-negative bacteria

Nonlinear intestinal pharmacokinetics of mitemcinal, the first acid-resistant non-peptide motilin receptor agonist, in rats

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