Usefulness of salivary drug monitoring for detectign efflux transporter overexpression
- Autores
- Fagiolino, Pietro; Vazquez, Marta; Maldonado, Cecilia; Ruiz, María Esperanza; Volonté, Maria Guillermina; Orozco Suárez, Sandra; Lazarowski, Alberto Jorge
- Año de publicación
- 2013
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Background: Bioavailability (F) and clearance (CL) are two pharmacokinetic parameters difficult to differentiate from simple plasma measurement when a drug is administered orally. Venous (V) / artery (A) concentration ratio of a drug could be a reliable index of its CL if measurements of plasma concentration were performed during a period of time where the absorption process was not longer operative, then during a pure elimination phase. Objective: A novel subrogate using two protocolized saliva samples sequentially collected (first, S1, and second, S2) was designed in order to replace V and A free plasma drug concentrations, respectively. Two drugs, phenytoin (PHT) and carbamazepine (CBZ), which are well-known for their inducer properties and their dose-dependent clearance variations, were studied taking into account the sex of individuals. Setting and patients: A multicentre two-phase collaborative study was done. The first phase was performed with healthy volunteers in order to determine salivary pharmacokinetic parameters after single dose administration. Twelve volunteers (6 male and 6 female) received 400 mg of CBZ (2 tablets x 200 mg, immediate release product). Twenty four volunteers (10 male and 14 female) received 100 mg of PHT. The second phase was carried out with epileptic patients under CBZ (11 male 15 female) or PHT (11 male and 11 female) monotherapy, in order to study dose-related and sex-related pharmacokinetic differences. Main outcome measures: In the single dose trials, peaks (Tmax, Cmax) were computed directly from the data. Areas under concentrationtime curves (AUC∞), AUC∞xW (area corrected by weight) and half-lives (t1/2) were calculated. In the case of CBZ, AUCCBZ-10,11- epoxide/AUCCBZ metabolic ratios were also calculated. After multiple dose administration, S1 and S2 trough morning drug concentrations were measured. Results: Cmax and AUC differed significantly between sexes for the two drugs after single dose administration. Nevertheless, the apparent clearance (CL/F) per unit of body weight did not differ (CBZ) or slightly differed (PHT) between sexes. Higher metabolic ratio for CBZ in women would lead to lower F and therefore lower CL in this gender. In the case of PHT, women would have either lower F or higher CL than men. After multiple dose administration, S1/S2 saliva drug concentration ratio correlated positively with S2 for CBZ, showing that CBZ clearance increases with daily dose. Gender differences were also observed for CBZ-10,11-epoxide concentration, being bioavailability the main parameter responsible for this difference. S1/S2 saliva PHT concentration ratio correlated negatively with S2, showing that PHT clearance diminishes with dose as it has been previously reported. Since a significant difference was found for S1/S2 ratio between male and females, CL is the pharmacokinetic parameter influenced by gender in PHT disposition. Conclusion: S1/S2 saliva drug concentration ratio was sensitive enough for detecting systemic clearance changes. Both CBZ and PHT would modify their bioavailability and clearance by inducing efflux transporter throughout chronic treatments, from the first dose to multiple dose administration.
Fil: Fagiolino, Pietro. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceuticas; Uruguay
Fil: Vazquez, Marta. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceutica; Uruguay
Fil: Maldonado, Cecilia. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceutica; Uruguay
Fil: Ruiz, María Esperanza. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Catedra de Control de Calidad de Medicamentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas; Argentina
Fil: Volonté, Maria Guillermina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Catedra de Control de Calidad de Medicamentos; Argentina
Fil: Orozco Suárez, Sandra. Centro Medico Nacional Siglo XXI del Instituto Mexicano del Seguro Social; México
Fil: Lazarowski, Alberto Jorge. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina - Materia
-
Saliva Drug Concentracion
Efflux Transporter Expression
Sex of Individuals
Bioavailability
Clearence
Carbamazepine
Phenytoin - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/4931
Ver los metadatos del registro completo
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Usefulness of salivary drug monitoring for detectign efflux transporter overexpressionFagiolino, PietroVazquez, MartaMaldonado, CeciliaRuiz, María EsperanzaVolonté, Maria GuillerminaOrozco Suárez, SandraLazarowski, Alberto JorgeSaliva Drug ConcentracionEfflux Transporter ExpressionSex of IndividualsBioavailabilityClearenceCarbamazepinePhenytoinhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: Bioavailability (F) and clearance (CL) are two pharmacokinetic parameters difficult to differentiate from simple plasma measurement when a drug is administered orally. Venous (V) / artery (A) concentration ratio of a drug could be a reliable index of its CL if measurements of plasma concentration were performed during a period of time where the absorption process was not longer operative, then during a pure elimination phase. Objective: A novel subrogate using two protocolized saliva samples sequentially collected (first, S1, and second, S2) was designed in order to replace V and A free plasma drug concentrations, respectively. Two drugs, phenytoin (PHT) and carbamazepine (CBZ), which are well-known for their inducer properties and their dose-dependent clearance variations, were studied taking into account the sex of individuals. Setting and patients: A multicentre two-phase collaborative study was done. The first phase was performed with healthy volunteers in order to determine salivary pharmacokinetic parameters after single dose administration. Twelve volunteers (6 male and 6 female) received 400 mg of CBZ (2 tablets x 200 mg, immediate release product). Twenty four volunteers (10 male and 14 female) received 100 mg of PHT. The second phase was carried out with epileptic patients under CBZ (11 male 15 female) or PHT (11 male and 11 female) monotherapy, in order to study dose-related and sex-related pharmacokinetic differences. Main outcome measures: In the single dose trials, peaks (Tmax, Cmax) were computed directly from the data. Areas under concentrationtime curves (AUC∞), AUC∞xW (area corrected by weight) and half-lives (t1/2) were calculated. In the case of CBZ, AUCCBZ-10,11- epoxide/AUCCBZ metabolic ratios were also calculated. After multiple dose administration, S1 and S2 trough morning drug concentrations were measured. Results: Cmax and AUC differed significantly between sexes for the two drugs after single dose administration. Nevertheless, the apparent clearance (CL/F) per unit of body weight did not differ (CBZ) or slightly differed (PHT) between sexes. Higher metabolic ratio for CBZ in women would lead to lower F and therefore lower CL in this gender. In the case of PHT, women would have either lower F or higher CL than men. After multiple dose administration, S1/S2 saliva drug concentration ratio correlated positively with S2 for CBZ, showing that CBZ clearance increases with daily dose. Gender differences were also observed for CBZ-10,11-epoxide concentration, being bioavailability the main parameter responsible for this difference. S1/S2 saliva PHT concentration ratio correlated negatively with S2, showing that PHT clearance diminishes with dose as it has been previously reported. Since a significant difference was found for S1/S2 ratio between male and females, CL is the pharmacokinetic parameter influenced by gender in PHT disposition. Conclusion: S1/S2 saliva drug concentration ratio was sensitive enough for detecting systemic clearance changes. Both CBZ and PHT would modify their bioavailability and clearance by inducing efflux transporter throughout chronic treatments, from the first dose to multiple dose administration.Fil: Fagiolino, Pietro. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceuticas; UruguayFil: Vazquez, Marta. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceutica; UruguayFil: Maldonado, Cecilia. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceutica; UruguayFil: Ruiz, María Esperanza. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Catedra de Control de Calidad de Medicamentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas; ArgentinaFil: Volonté, Maria Guillermina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Catedra de Control de Calidad de Medicamentos; ArgentinaFil: Orozco Suárez, Sandra. Centro Medico Nacional Siglo XXI del Instituto Mexicano del Seguro Social; MéxicoFil: Lazarowski, Alberto Jorge. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaBentham Science Publishers2013-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4931Fagiolino, Pietro; Vazquez, Marta; Maldonado, Cecilia; Ruiz, María Esperanza; Volonté, Maria Guillermina; et al.; Usefulness of salivary drug monitoring for detectign efflux transporter overexpression; Bentham Science Publishers; Current Pharmaceutical Design.; 19; 38; 9-2013; 6701-67081381-6128enginfo:eu-repo/semantics/altIdentifier/url/http://www.eurekaselect.com/108861/articleinfo:eu-repo/semantics/altIdentifier/doi/10.2174/13816128113199990368info:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/pmid/23530513info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:47:11Zoai:ri.conicet.gov.ar:11336/4931instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:47:11.438CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Usefulness of salivary drug monitoring for detectign efflux transporter overexpression |
title |
Usefulness of salivary drug monitoring for detectign efflux transporter overexpression |
spellingShingle |
Usefulness of salivary drug monitoring for detectign efflux transporter overexpression Fagiolino, Pietro Saliva Drug Concentracion Efflux Transporter Expression Sex of Individuals Bioavailability Clearence Carbamazepine Phenytoin |
title_short |
Usefulness of salivary drug monitoring for detectign efflux transporter overexpression |
title_full |
Usefulness of salivary drug monitoring for detectign efflux transporter overexpression |
title_fullStr |
Usefulness of salivary drug monitoring for detectign efflux transporter overexpression |
title_full_unstemmed |
Usefulness of salivary drug monitoring for detectign efflux transporter overexpression |
title_sort |
Usefulness of salivary drug monitoring for detectign efflux transporter overexpression |
dc.creator.none.fl_str_mv |
Fagiolino, Pietro Vazquez, Marta Maldonado, Cecilia Ruiz, María Esperanza Volonté, Maria Guillermina Orozco Suárez, Sandra Lazarowski, Alberto Jorge |
author |
Fagiolino, Pietro |
author_facet |
Fagiolino, Pietro Vazquez, Marta Maldonado, Cecilia Ruiz, María Esperanza Volonté, Maria Guillermina Orozco Suárez, Sandra Lazarowski, Alberto Jorge |
author_role |
author |
author2 |
Vazquez, Marta Maldonado, Cecilia Ruiz, María Esperanza Volonté, Maria Guillermina Orozco Suárez, Sandra Lazarowski, Alberto Jorge |
author2_role |
author author author author author author |
dc.subject.none.fl_str_mv |
Saliva Drug Concentracion Efflux Transporter Expression Sex of Individuals Bioavailability Clearence Carbamazepine Phenytoin |
topic |
Saliva Drug Concentracion Efflux Transporter Expression Sex of Individuals Bioavailability Clearence Carbamazepine Phenytoin |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Background: Bioavailability (F) and clearance (CL) are two pharmacokinetic parameters difficult to differentiate from simple plasma measurement when a drug is administered orally. Venous (V) / artery (A) concentration ratio of a drug could be a reliable index of its CL if measurements of plasma concentration were performed during a period of time where the absorption process was not longer operative, then during a pure elimination phase. Objective: A novel subrogate using two protocolized saliva samples sequentially collected (first, S1, and second, S2) was designed in order to replace V and A free plasma drug concentrations, respectively. Two drugs, phenytoin (PHT) and carbamazepine (CBZ), which are well-known for their inducer properties and their dose-dependent clearance variations, were studied taking into account the sex of individuals. Setting and patients: A multicentre two-phase collaborative study was done. The first phase was performed with healthy volunteers in order to determine salivary pharmacokinetic parameters after single dose administration. Twelve volunteers (6 male and 6 female) received 400 mg of CBZ (2 tablets x 200 mg, immediate release product). Twenty four volunteers (10 male and 14 female) received 100 mg of PHT. The second phase was carried out with epileptic patients under CBZ (11 male 15 female) or PHT (11 male and 11 female) monotherapy, in order to study dose-related and sex-related pharmacokinetic differences. Main outcome measures: In the single dose trials, peaks (Tmax, Cmax) were computed directly from the data. Areas under concentrationtime curves (AUC∞), AUC∞xW (area corrected by weight) and half-lives (t1/2) were calculated. In the case of CBZ, AUCCBZ-10,11- epoxide/AUCCBZ metabolic ratios were also calculated. After multiple dose administration, S1 and S2 trough morning drug concentrations were measured. Results: Cmax and AUC differed significantly between sexes for the two drugs after single dose administration. Nevertheless, the apparent clearance (CL/F) per unit of body weight did not differ (CBZ) or slightly differed (PHT) between sexes. Higher metabolic ratio for CBZ in women would lead to lower F and therefore lower CL in this gender. In the case of PHT, women would have either lower F or higher CL than men. After multiple dose administration, S1/S2 saliva drug concentration ratio correlated positively with S2 for CBZ, showing that CBZ clearance increases with daily dose. Gender differences were also observed for CBZ-10,11-epoxide concentration, being bioavailability the main parameter responsible for this difference. S1/S2 saliva PHT concentration ratio correlated negatively with S2, showing that PHT clearance diminishes with dose as it has been previously reported. Since a significant difference was found for S1/S2 ratio between male and females, CL is the pharmacokinetic parameter influenced by gender in PHT disposition. Conclusion: S1/S2 saliva drug concentration ratio was sensitive enough for detecting systemic clearance changes. Both CBZ and PHT would modify their bioavailability and clearance by inducing efflux transporter throughout chronic treatments, from the first dose to multiple dose administration. Fil: Fagiolino, Pietro. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceuticas; Uruguay Fil: Vazquez, Marta. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceutica; Uruguay Fil: Maldonado, Cecilia. Universidad de la República. Facultad de química. Departamentos de Ciencias Farmaceutica; Uruguay Fil: Ruiz, María Esperanza. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Catedra de Control de Calidad de Medicamentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas; Argentina Fil: Volonté, Maria Guillermina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Catedra de Control de Calidad de Medicamentos; Argentina Fil: Orozco Suárez, Sandra. Centro Medico Nacional Siglo XXI del Instituto Mexicano del Seguro Social; México Fil: Lazarowski, Alberto Jorge. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina |
description |
Background: Bioavailability (F) and clearance (CL) are two pharmacokinetic parameters difficult to differentiate from simple plasma measurement when a drug is administered orally. Venous (V) / artery (A) concentration ratio of a drug could be a reliable index of its CL if measurements of plasma concentration were performed during a period of time where the absorption process was not longer operative, then during a pure elimination phase. Objective: A novel subrogate using two protocolized saliva samples sequentially collected (first, S1, and second, S2) was designed in order to replace V and A free plasma drug concentrations, respectively. Two drugs, phenytoin (PHT) and carbamazepine (CBZ), which are well-known for their inducer properties and their dose-dependent clearance variations, were studied taking into account the sex of individuals. Setting and patients: A multicentre two-phase collaborative study was done. The first phase was performed with healthy volunteers in order to determine salivary pharmacokinetic parameters after single dose administration. Twelve volunteers (6 male and 6 female) received 400 mg of CBZ (2 tablets x 200 mg, immediate release product). Twenty four volunteers (10 male and 14 female) received 100 mg of PHT. The second phase was carried out with epileptic patients under CBZ (11 male 15 female) or PHT (11 male and 11 female) monotherapy, in order to study dose-related and sex-related pharmacokinetic differences. Main outcome measures: In the single dose trials, peaks (Tmax, Cmax) were computed directly from the data. Areas under concentrationtime curves (AUC∞), AUC∞xW (area corrected by weight) and half-lives (t1/2) were calculated. In the case of CBZ, AUCCBZ-10,11- epoxide/AUCCBZ metabolic ratios were also calculated. After multiple dose administration, S1 and S2 trough morning drug concentrations were measured. Results: Cmax and AUC differed significantly between sexes for the two drugs after single dose administration. Nevertheless, the apparent clearance (CL/F) per unit of body weight did not differ (CBZ) or slightly differed (PHT) between sexes. Higher metabolic ratio for CBZ in women would lead to lower F and therefore lower CL in this gender. In the case of PHT, women would have either lower F or higher CL than men. After multiple dose administration, S1/S2 saliva drug concentration ratio correlated positively with S2 for CBZ, showing that CBZ clearance increases with daily dose. Gender differences were also observed for CBZ-10,11-epoxide concentration, being bioavailability the main parameter responsible for this difference. S1/S2 saliva PHT concentration ratio correlated negatively with S2, showing that PHT clearance diminishes with dose as it has been previously reported. Since a significant difference was found for S1/S2 ratio between male and females, CL is the pharmacokinetic parameter influenced by gender in PHT disposition. Conclusion: S1/S2 saliva drug concentration ratio was sensitive enough for detecting systemic clearance changes. Both CBZ and PHT would modify their bioavailability and clearance by inducing efflux transporter throughout chronic treatments, from the first dose to multiple dose administration. |
publishDate |
2013 |
dc.date.none.fl_str_mv |
2013-09 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/4931 Fagiolino, Pietro; Vazquez, Marta; Maldonado, Cecilia; Ruiz, María Esperanza; Volonté, Maria Guillermina; et al.; Usefulness of salivary drug monitoring for detectign efflux transporter overexpression; Bentham Science Publishers; Current Pharmaceutical Design.; 19; 38; 9-2013; 6701-6708 1381-6128 |
url |
http://hdl.handle.net/11336/4931 |
identifier_str_mv |
Fagiolino, Pietro; Vazquez, Marta; Maldonado, Cecilia; Ruiz, María Esperanza; Volonté, Maria Guillermina; et al.; Usefulness of salivary drug monitoring for detectign efflux transporter overexpression; Bentham Science Publishers; Current Pharmaceutical Design.; 19; 38; 9-2013; 6701-6708 1381-6128 |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://www.eurekaselect.com/108861/article info:eu-repo/semantics/altIdentifier/doi/10.2174/13816128113199990368 info:eu-repo/semantics/altIdentifier/doi/ info:eu-repo/semantics/altIdentifier/pmid/23530513 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Bentham Science Publishers |
publisher.none.fl_str_mv |
Bentham Science Publishers |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613470838849536 |
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13.070432 |