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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4931

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oai_identifier_str oai:ri.conicet.gov.ar:11336/4931
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv 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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