In Vitro Characterization of the Erythrocyte Distribution of Methazolamide: A Model of Erythrocyte Transport and Binding Kinetics
Identifieur interne : 002665 ( Main/Exploration ); précédent : 002664; suivant : 002666In Vitro Characterization of the Erythrocyte Distribution of Methazolamide: A Model of Erythrocyte Transport and Binding Kinetics
Auteurs : Ganesh R. Iyer [États-Unis] ; Robert A. Bellantone [États-Unis] ; David R. Taft [États-Unis]Source :
- Journal of Pharmacokinetics and Biopharmaceutics [ 0090-466X ] ; 1999-02-01.
English descriptors
Abstract
Abstract: The rate and extent of binding of methazolamide to human erythrocytes was studied in vitro. All experiments were carried out at physiological temperature (37C) and pH (7.4). Methazolamide (MTZ) buffer concentrations were analyzed by HPLC. Distributional equilibrium between buffer and washed red blood cells was achieved after 1 hr. Results of equilibrium studies were consistent with two classes of binding sites for MTZ within the erythrocyte: a low affinity, high capacity site (CA-I) and a high affinity, low capacity site (CA-II). A two-binding site model was fitted to experimental data generating estimates for binding parameters Ka1 (0.0017 ± 0.00022 μM −1 ) nM1 (636 ± 5.23 μM), Ka2 (0.46 ± 0.0083 μM −1 ), and nM2 (80.9 ± 0.389 μM). Based upon these findings, kinetic studies were performed in order to characterize the rate of drug distribution. The rate of erythrocyte uptake of MTZ was mathematically modeled using a series of differential equations describing drug diffusion across the red blood cell membrane and subsequent complexation with intracellular binding sites. The model assumed that penetration of MTZ into the red blood cells was passive but drug binding to the carbonic anhydrase isozymes was not instantaneous. Using a novel curve fitting technique, parameter estimates of RBC membrane permeability (0.0102 ± 0.000618 cm/min), and binding rate constants k−1 (0.254 ± 0.0213 min −1 ), k1 (0.0022 ± 0.00020 ml/μg-min), k−2 (1.59 ± 0.0358 min −1 ), and k2 (3.1 ± 0.035 ml/μg-min) were obtained. The model characterized the observed biphasic decline of MTZ buffer concentrations over time and may help explain the prolonged residence of MTZ in vivo.
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DOI: 10.1023/A:1020630712388
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Iyer</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Division of Pharmaceutics and Industrial Pharmacy, Long Island University, University Plaza, 11201, Brooklyn</wicri:cityArea></affiliation></author><author><name sortKey="Bellantone, Robert A" sort="Bellantone, Robert A" uniqKey="Bellantone R" first="Robert A." last="Bellantone">Robert A. Bellantone</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Division of Pharmaceutics and Industrial Pharmacy, Long Island University, University Plaza, 11201, Brooklyn</wicri:cityArea></affiliation></author><author><name sortKey="Taft, David R" sort="Taft, David R" uniqKey="Taft D" first="David R." last="Taft">David R. 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All experiments were carried out at physiological temperature (37C) and pH (7.4). Methazolamide (MTZ) buffer concentrations were analyzed by HPLC. Distributional equilibrium between buffer and washed red blood cells was achieved after 1 hr. Results of equilibrium studies were consistent with two classes of binding sites for MTZ within the erythrocyte: a low affinity, high capacity site (CA-I) and a high affinity, low capacity site (CA-II). A two-binding site model was fitted to experimental data generating estimates for binding parameters Ka1 (0.0017 ± 0.00022 μM −1 ) nM1 (636 ± 5.23 μM), Ka2 (0.46 ± 0.0083 μM −1 ), and nM2 (80.9 ± 0.389 μM). Based upon these findings, kinetic studies were performed in order to characterize the rate of drug distribution. The rate of erythrocyte uptake of MTZ was mathematically modeled using a series of differential equations describing drug diffusion across the red blood cell membrane and subsequent complexation with intracellular binding sites. The model assumed that penetration of MTZ into the red blood cells was passive but drug binding to the carbonic anhydrase isozymes was not instantaneous. Using a novel curve fitting technique, parameter estimates of RBC membrane permeability (0.0102 ± 0.000618 cm/min), and binding rate constants k−1 (0.254 ± 0.0213 min −1 ), k1 (0.0022 ± 0.00020 ml/μg-min), k−2 (1.59 ± 0.0358 min −1 ), and k2 (3.1 ± 0.035 ml/μg-min) were obtained. The model characterized the observed biphasic decline of MTZ buffer concentrations over time and may help explain the prolonged residence of MTZ in vivo.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>État de New York</li></region></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Iyer, Ganesh R" sort="Iyer, Ganesh R" uniqKey="Iyer G" first="Ganesh R." last="Iyer">Ganesh R. 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