The Experts below are selected from a list of 924 Experts worldwide ranked by ideXlab platform
Jean-pierre Montenez - One of the best experts on this subject based on the ideXlab platform.
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interactions of macrolide antibiotics erythromycin a roxithromycin erythromycylamine dirithromycin and azithromycin with phospholipids computer aided conformational analysis and studies on acellular and cell culture models
Toxicology and Applied Pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, M P MingeotleclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A Phospholipidosis (affecting all major phospholipids except sphingomyelin) was observed after 3 days with the following ranking: erythromycin A toxicity). The difference between erythromycylamine and azithromycin was accounted for by the lower cellular accumulation of erythromycylamine. In parallel, based on a methodology developed and validated to study drug-membrane interactions, the conformational analyses revealed that erythromycin A, roxithromycin, erythromycylamine, and azithromycin penetrate into the hydrophobic domain of a phosphatidylinositol monolayer through their desosamine and cladinose moieties, whereas their macrocycle is found close to the interface. This position allows the aminogroups carried by the macrocycle of the diaminated macrolides (erythromycylamine and azithromycin) to come into close contact with the negatively charged phosphogroup of phosphatidylinositol, whereas the amine located on the C-3 of the desosamine, common to all four drugs, is located at a greater distance from this phosphogroup. Our study suggests that all macrolides have the potential to cause Phospholipidosis but that this effect is modulated by toxicodynamic and toxicokinetic parameters related to the drug structure and mainly to their cationic character.
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Interactions of macrolide antibiotics (Erythromycin A, roxithromycin, erythromycylamine [Dirithromycin], and azithromycin) with phospholipids: computer-aided conformational analysis and studies on acellular and cell culture models.
Toxicology and applied pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A
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Interactions Of Macrolide Antibiotics (Erythromycin A, Roxithromycin, Erythromycylamine [Dirithromycin], And Azithromycin) With Phospholipids: Computer-Aided Conformational Analysis And Studies On Acellular And Cell Culture Models
'Elsevier BV', 1999Co-Authors: Jean-pierre Montenez, Paul M. Tulkens, Vanbambeke F., Piret J., Brasseur Robert, Mingeot-leclercq Marie-pauleAbstract:peer reviewedaudience: researcher, professionalThe potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A
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Interaction of the macrolide azithromycin with phospholipids. II. Biophysical and computer-aided conformational studies
European Journal of Pharmacology, 1996Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, André Schanck, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:In a comparison paper, we show the azithromycin causes a lysosomal Phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits lysosomal phospholipase A1. In this paper, we show that azithromycin decreases the mobility of the phospholipids in negatively charged liposomes (using 31P nuclear magnetic resonance) and that it increases the fluidity of the acyl chains close to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene and diphenyhexatriene, respectively). Computer-aided conformational analysis of mixed monolayers of azithromycin and phosphatidylinositol shows that the drug can be positioned largely in the hydrophobic domain, but close to the interface, with the macrocycle facing the C1 of the fatty acids (allowing the N9a endocyclic tertiary amine to interact with the phospho-groups), the cladinose located on the hydrophobic side of the lipid/water interface and the desosamine projected into the hydrophobic domain. This position is consistent with the experimental data. Analysis of virtual molecules shows that this unanticipated behavior to the shielding of the ionizable N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion of hydrophobic domains all over the molecule. The interaction of azithromycin with phospholipids may account for some of its unusual pharmacokinetic properties and for its potential to cause lysosomal Phospholipidosis.
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Interaction Of The Macrolide Azithromycin With Phospholipids .2. Biophysical And Computer-Aided Conformational Studies
'Elsevier BV', 1996Co-Authors: Jean-pierre Montenez, Paul M. Tulkens, Vanbambeke F., Piret J., Schanck A., Brasseur Robert, Mingeot-leclercq Marie-pauleAbstract:peer reviewedaudience: researcher, professionalIn a comparison paper, we show the azithromycin causes a lysosomal Phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits lysosomal phospholipase A1. In this paper, we show that azithromycin decreases the mobility of the phospholipids in negatively charged liposomes (using 31P nuclear magnetic resonance) and that it increases the fluidity of the acyl chains close to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene and diphenyhexatriene, respectively). Computer-aided conformational analysis of mixed monolayers of azithromycin and phosphatidylinositol shows that the drug can be positioned largely in the hydrophobic domain, but close to the interface, with the macrocycle facing the C1 of the fatty acids (allowing the N9a endocyclic tertiary amine to interact with the phospho-groups), the cladinose located on the hydrophobic side of the lipid/water interface and the desosamine projected into the hydrophobic domain. This position is consistent with the experimental data. Analysis of virtual molecules shows that this unanticipated behavior to the shielding of the ionizable N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion of hydrophobic domains all over the molecule. The interaction of azithromycin with phospholipids may account for some of its unusual pharmacokinetic properties and for its potential to cause lysosomal Phospholipidosis
Marie-paule Mingeot-leclercq - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis in renal proximal tubules of rats treated with low doses of aminoglycosides. Antimicrob. Agents Chemother
2000Co-Authors: Mohammed El Mouedden, Marie-paule Mingeot-leclercq, Guy Laurent, Henryk S. Taper, Jean Cumps, Paul M. TulkensAbstract:Kidney cortex apoptosis was studied with female Wistar rats treated for 10 days with gentamicin and netilmicin at daily doses of 10 or 20 mg/kg of body weight and amikacin or isepamicin at daily doses of 40 mg/kg. Apoptosis was detected and quantitated using cytological (methyl green-pyronine) and immunohistochemical (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining, in parallel with a measurement of drug-induced Phospholipidosis (cortical phospholipids and phospholipiduria), cortical proliferative response ( 3 H incorporation in DNA and histoautoradiography after in vivo pulse-labeling with [ 3 H]thymidine), and kidney dysfunction (blood urea nitrogen and creatinine). Gentamicin induced in proximal tubules a marked apoptotic reaction which (i) was detectable after 4 days of treatment but was most conspicuous after 10 days, (ii) was dose dependent, (iii) occurred in the absence of necrosis, and (iv) was nonlinearly correlated with the proliferative response (tubular and peritubular cells). Comparative studies revealed a parallelism among the extents of Phospholipidosis, apoptosis, and proliferative response for three aminoglycosides (gentamicin>> amikacin � isepamicin). By contrast, netilmicin induced a marked Phospholipidosis but a moderate apoptosis and proliferative response. We conclude that rats treated with gentamicin develop an apoptotic process as part of the various cortical alterations induced by this antibiotic at low doses. Netilmicin, and still more amikacin and isepamicin, appears safer in this respect. Whereas a relation between aminoglycoside-induce
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Interactions of macrolide antibiotics (Erythromycin A, roxithromycin, erythromycylamine [Dirithromycin], and azithromycin) with phospholipids: computer-aided conformational analysis and studies on acellular and cell culture models.
Toxicology and applied pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A
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Interaction of the macrolide azithromycin with phospholipids. II. Biophysical and computer-aided conformational studies
European Journal of Pharmacology, 1996Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, André Schanck, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:In a comparison paper, we show the azithromycin causes a lysosomal Phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits lysosomal phospholipase A1. In this paper, we show that azithromycin decreases the mobility of the phospholipids in negatively charged liposomes (using 31P nuclear magnetic resonance) and that it increases the fluidity of the acyl chains close to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene and diphenyhexatriene, respectively). Computer-aided conformational analysis of mixed monolayers of azithromycin and phosphatidylinositol shows that the drug can be positioned largely in the hydrophobic domain, but close to the interface, with the macrocycle facing the C1 of the fatty acids (allowing the N9a endocyclic tertiary amine to interact with the phospho-groups), the cladinose located on the hydrophobic side of the lipid/water interface and the desosamine projected into the hydrophobic domain. This position is consistent with the experimental data. Analysis of virtual molecules shows that this unanticipated behavior to the shielding of the ionizable N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion of hydrophobic domains all over the molecule. The interaction of azithromycin with phospholipids may account for some of its unusual pharmacokinetic properties and for its potential to cause lysosomal Phospholipidosis.
Paul M. Tulkens - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis in renal proximal tubules of rats treated with low doses of aminoglycosides. Antimicrob. Agents Chemother
2000Co-Authors: Mohammed El Mouedden, Marie-paule Mingeot-leclercq, Guy Laurent, Henryk S. Taper, Jean Cumps, Paul M. TulkensAbstract:Kidney cortex apoptosis was studied with female Wistar rats treated for 10 days with gentamicin and netilmicin at daily doses of 10 or 20 mg/kg of body weight and amikacin or isepamicin at daily doses of 40 mg/kg. Apoptosis was detected and quantitated using cytological (methyl green-pyronine) and immunohistochemical (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining, in parallel with a measurement of drug-induced Phospholipidosis (cortical phospholipids and phospholipiduria), cortical proliferative response ( 3 H incorporation in DNA and histoautoradiography after in vivo pulse-labeling with [ 3 H]thymidine), and kidney dysfunction (blood urea nitrogen and creatinine). Gentamicin induced in proximal tubules a marked apoptotic reaction which (i) was detectable after 4 days of treatment but was most conspicuous after 10 days, (ii) was dose dependent, (iii) occurred in the absence of necrosis, and (iv) was nonlinearly correlated with the proliferative response (tubular and peritubular cells). Comparative studies revealed a parallelism among the extents of Phospholipidosis, apoptosis, and proliferative response for three aminoglycosides (gentamicin>> amikacin � isepamicin). By contrast, netilmicin induced a marked Phospholipidosis but a moderate apoptosis and proliferative response. We conclude that rats treated with gentamicin develop an apoptotic process as part of the various cortical alterations induced by this antibiotic at low doses. Netilmicin, and still more amikacin and isepamicin, appears safer in this respect. Whereas a relation between aminoglycoside-induce
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interactions of macrolide antibiotics erythromycin a roxithromycin erythromycylamine dirithromycin and azithromycin with phospholipids computer aided conformational analysis and studies on acellular and cell culture models
Toxicology and Applied Pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, M P MingeotleclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A Phospholipidosis (affecting all major phospholipids except sphingomyelin) was observed after 3 days with the following ranking: erythromycin A toxicity). The difference between erythromycylamine and azithromycin was accounted for by the lower cellular accumulation of erythromycylamine. In parallel, based on a methodology developed and validated to study drug-membrane interactions, the conformational analyses revealed that erythromycin A, roxithromycin, erythromycylamine, and azithromycin penetrate into the hydrophobic domain of a phosphatidylinositol monolayer through their desosamine and cladinose moieties, whereas their macrocycle is found close to the interface. This position allows the aminogroups carried by the macrocycle of the diaminated macrolides (erythromycylamine and azithromycin) to come into close contact with the negatively charged phosphogroup of phosphatidylinositol, whereas the amine located on the C-3 of the desosamine, common to all four drugs, is located at a greater distance from this phosphogroup. Our study suggests that all macrolides have the potential to cause Phospholipidosis but that this effect is modulated by toxicodynamic and toxicokinetic parameters related to the drug structure and mainly to their cationic character.
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Interactions of macrolide antibiotics (Erythromycin A, roxithromycin, erythromycylamine [Dirithromycin], and azithromycin) with phospholipids: computer-aided conformational analysis and studies on acellular and cell culture models.
Toxicology and applied pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A
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Interactions Of Macrolide Antibiotics (Erythromycin A, Roxithromycin, Erythromycylamine [Dirithromycin], And Azithromycin) With Phospholipids: Computer-Aided Conformational Analysis And Studies On Acellular And Cell Culture Models
'Elsevier BV', 1999Co-Authors: Jean-pierre Montenez, Paul M. Tulkens, Vanbambeke F., Piret J., Brasseur Robert, Mingeot-leclercq Marie-pauleAbstract:peer reviewedaudience: researcher, professionalThe potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A
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Interaction of the macrolide azithromycin with phospholipids. II. Biophysical and computer-aided conformational studies
European Journal of Pharmacology, 1996Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, André Schanck, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:In a comparison paper, we show the azithromycin causes a lysosomal Phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits lysosomal phospholipase A1. In this paper, we show that azithromycin decreases the mobility of the phospholipids in negatively charged liposomes (using 31P nuclear magnetic resonance) and that it increases the fluidity of the acyl chains close to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene and diphenyhexatriene, respectively). Computer-aided conformational analysis of mixed monolayers of azithromycin and phosphatidylinositol shows that the drug can be positioned largely in the hydrophobic domain, but close to the interface, with the macrocycle facing the C1 of the fatty acids (allowing the N9a endocyclic tertiary amine to interact with the phospho-groups), the cladinose located on the hydrophobic side of the lipid/water interface and the desosamine projected into the hydrophobic domain. This position is consistent with the experimental data. Analysis of virtual molecules shows that this unanticipated behavior to the shielding of the ionizable N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion of hydrophobic domains all over the molecule. The interaction of azithromycin with phospholipids may account for some of its unusual pharmacokinetic properties and for its potential to cause lysosomal Phospholipidosis.
Françoise Van Bambeke - One of the best experts on this subject based on the ideXlab platform.
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Interactions of macrolide antibiotics (Erythromycin A, roxithromycin, erythromycylamine [Dirithromycin], and azithromycin) with phospholipids: computer-aided conformational analysis and studies on acellular and cell culture models.
Toxicology and applied pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A
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interactions of macrolide antibiotics erythromycin a roxithromycin erythromycylamine dirithromycin and azithromycin with phospholipids computer aided conformational analysis and studies on acellular and cell culture models
Toxicology and Applied Pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, M P MingeotleclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A Phospholipidosis (affecting all major phospholipids except sphingomyelin) was observed after 3 days with the following ranking: erythromycin A toxicity). The difference between erythromycylamine and azithromycin was accounted for by the lower cellular accumulation of erythromycylamine. In parallel, based on a methodology developed and validated to study drug-membrane interactions, the conformational analyses revealed that erythromycin A, roxithromycin, erythromycylamine, and azithromycin penetrate into the hydrophobic domain of a phosphatidylinositol monolayer through their desosamine and cladinose moieties, whereas their macrocycle is found close to the interface. This position allows the aminogroups carried by the macrocycle of the diaminated macrolides (erythromycylamine and azithromycin) to come into close contact with the negatively charged phosphogroup of phosphatidylinositol, whereas the amine located on the C-3 of the desosamine, common to all four drugs, is located at a greater distance from this phosphogroup. Our study suggests that all macrolides have the potential to cause Phospholipidosis but that this effect is modulated by toxicodynamic and toxicokinetic parameters related to the drug structure and mainly to their cationic character.
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Interaction of the macrolide azithromycin with phospholipids. II. Biophysical and computer-aided conformational studies
European Journal of Pharmacology, 1996Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, André Schanck, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:In a comparison paper, we show the azithromycin causes a lysosomal Phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits lysosomal phospholipase A1. In this paper, we show that azithromycin decreases the mobility of the phospholipids in negatively charged liposomes (using 31P nuclear magnetic resonance) and that it increases the fluidity of the acyl chains close to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene and diphenyhexatriene, respectively). Computer-aided conformational analysis of mixed monolayers of azithromycin and phosphatidylinositol shows that the drug can be positioned largely in the hydrophobic domain, but close to the interface, with the macrocycle facing the C1 of the fatty acids (allowing the N9a endocyclic tertiary amine to interact with the phospho-groups), the cladinose located on the hydrophobic side of the lipid/water interface and the desosamine projected into the hydrophobic domain. This position is consistent with the experimental data. Analysis of virtual molecules shows that this unanticipated behavior to the shielding of the ionizable N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion of hydrophobic domains all over the molecule. The interaction of azithromycin with phospholipids may account for some of its unusual pharmacokinetic properties and for its potential to cause lysosomal Phospholipidosis.
Jocelyne Piret - One of the best experts on this subject based on the ideXlab platform.
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Interactions of macrolide antibiotics (Erythromycin A, roxithromycin, erythromycylamine [Dirithromycin], and azithromycin) with phospholipids: computer-aided conformational analysis and studies on acellular and cell culture models.
Toxicology and applied pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A
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interactions of macrolide antibiotics erythromycin a roxithromycin erythromycylamine dirithromycin and azithromycin with phospholipids computer aided conformational analysis and studies on acellular and cell culture models
Toxicology and Applied Pharmacology, 1999Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, Robert Brasseur, M P MingeotleclercqAbstract:The potential of 14/15 membered macrolides to cause Phospholipidosis has been prospectively assessed, and structure-effects examined, using combined experimental and conformational approaches. Biochemical studies demonstrated drug binding to phosphatidylinositol-containing liposomes and inhibition of the activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the bilayer, in close correlation with the number of cationic groups carried by the drugs (erythromycin A Phospholipidosis (affecting all major phospholipids except sphingomyelin) was observed after 3 days with the following ranking: erythromycin A toxicity). The difference between erythromycylamine and azithromycin was accounted for by the lower cellular accumulation of erythromycylamine. In parallel, based on a methodology developed and validated to study drug-membrane interactions, the conformational analyses revealed that erythromycin A, roxithromycin, erythromycylamine, and azithromycin penetrate into the hydrophobic domain of a phosphatidylinositol monolayer through their desosamine and cladinose moieties, whereas their macrocycle is found close to the interface. This position allows the aminogroups carried by the macrocycle of the diaminated macrolides (erythromycylamine and azithromycin) to come into close contact with the negatively charged phosphogroup of phosphatidylinositol, whereas the amine located on the C-3 of the desosamine, common to all four drugs, is located at a greater distance from this phosphogroup. Our study suggests that all macrolides have the potential to cause Phospholipidosis but that this effect is modulated by toxicodynamic and toxicokinetic parameters related to the drug structure and mainly to their cationic character.
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Interaction of the macrolide azithromycin with phospholipids. II. Biophysical and computer-aided conformational studies
European Journal of Pharmacology, 1996Co-Authors: Jean-pierre Montenez, Françoise Van Bambeke, Paul M. Tulkens, Jocelyne Piret, André Schanck, Robert Brasseur, Marie-paule Mingeot-leclercqAbstract:In a comparison paper, we show the azithromycin causes a lysosomal Phospholipidosis in cultured cells, binds in vitro to negatively charged bilayers without causing aggregation or fusion, and inhibits lysosomal phospholipase A1. In this paper, we show that azithromycin decreases the mobility of the phospholipids in negatively charged liposomes (using 31P nuclear magnetic resonance) and that it increases the fluidity of the acyl chains close to the hydrophilic/hydrophobic interface, but not deeper into the hydrophobic domain (assessed by measuring the fluorescence polarization of trimethylammonium-diphenylhexatriene and diphenyhexatriene, respectively). Computer-aided conformational analysis of mixed monolayers of azithromycin and phosphatidylinositol shows that the drug can be positioned largely in the hydrophobic domain, but close to the interface, with the macrocycle facing the C1 of the fatty acids (allowing the N9a endocyclic tertiary amine to interact with the phospho-groups), the cladinose located on the hydrophobic side of the lipid/water interface and the desosamine projected into the hydrophobic domain. This position is consistent with the experimental data. Analysis of virtual molecules shows that this unanticipated behavior to the shielding of the ionizable N3' amino-group in the desosamine by methyl-groups, and to the wide dispersion of hydrophobic domains all over the molecule. The interaction of azithromycin with phospholipids may account for some of its unusual pharmacokinetic properties and for its potential to cause lysosomal Phospholipidosis.