Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters

The metabolic syndrome in HIV infected patients is particularly associated with the use protease inhibitors. Atazanavir is an inhibitor of the cytochrome P 450 (CYP) system, in particular CYP3A4 and CYP2C9 which can affect the metabolism of several drugs. To treat metabolic syndrome in HIV patients...

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Main Authors: Thirumal Eswara Goud, Srinivas Maddi, Nayakanti Devanna, Thatipamula Rajendra Prasad
Format: Article
Language:English
Published: International Association of Physical Chemists (IAPC) 2016-10-01
Series:ADMET and DMPK
Subjects:
Online Access:http://pub.iapchem.org/ojs/index.php/admet/article/view/328
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spelling doaj-b8c71fb0527f47ada9ca784f85c07c9c2020-11-24T23:48:17ZengInternational Association of Physical Chemists (IAPC)ADMET and DMPK1848-77182016-10-014326927910.5599/admet.4.3.328224Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transportersThirumal Eswara Goud0Srinivas MaddiNayakanti DevannaThatipamula Rajendra PrasadCREATIVE EDUCATIONAL SOCIETY'S COLLEGE OF PHARMACY, KURNOOL, ANDHRA PRADESH, INDIAThe metabolic syndrome in HIV infected patients is particularly associated with the use protease inhibitors. Atazanavir is an inhibitor of the cytochrome P 450 (CYP) system, in particular CYP3A4 and CYP2C9 which can affect the metabolism of several drugs. To treat metabolic syndrome in HIV patients repaglinide is used and it is a short acting insulin secretagogues undergoing metabolism with CYP 3A4 and CYP 2C8 enzyme system. The purpose of this study was to assess the possible pharmacokinetic and pharmacodynamic drug interaction of repaglinide and atazanavir in healthy, diabetic and impaired hepatic function rats. Human oral therapeutic doses of atazanavir and repaglinide were extrapolated to rats based on the body surface area. The pharmacokinetic parameters and blood glucose concentrations of repaglinide were determined after oral administration of repaglinide alone (0.5 mg/kg) and in the presence of atazanavir (36 mg/kg) in normal, diabetic and hepatic impaired rats. The pharmacokinetics (PK) and blood glucose concentrations of repaglinide were significantly altered in the presence of atazanavir. The peak plasma concentration (Cmax), area under the plasma concentration time profile (AUC) and elimination half-life of repaglinide were significantly (P<0.0001) increased. The repaglinide clearance (CL) was significantly (P<0.0001) decreased in the presence of atazanavir treatment. In the presence of atazanavir, repaglinide hypoglycaemic activity was increased significantly (P<0.0001) when compared with the repaglinide control group. The present study demonstrated the significant difference in the PK/PD changes due to the enhanced bioavailability and decreased total body clearance of repaglinide may be due to the inhibition of the CYP P450 metabolic system, OATP and P-gp transporters by atazanavir.http://pub.iapchem.org/ojs/index.php/admet/article/view/328AIDSDrug drug interactionhypoglycaemic activityLiver dysfunctionPeak plasma concentration CmaxArea under the curve AucClearanceElimination half life.
collection DOAJ
language English
format Article
sources DOAJ
author Thirumal Eswara Goud
Srinivas Maddi
Nayakanti Devanna
Thatipamula Rajendra Prasad
spellingShingle Thirumal Eswara Goud
Srinivas Maddi
Nayakanti Devanna
Thatipamula Rajendra Prasad
Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters
ADMET and DMPK
AIDS
Drug drug interaction
hypoglycaemic activity
Liver dysfunction
Peak plasma concentration Cmax
Area under the curve Auc
Clearance
Elimination half life.
author_facet Thirumal Eswara Goud
Srinivas Maddi
Nayakanti Devanna
Thatipamula Rajendra Prasad
author_sort Thirumal Eswara Goud
title Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters
title_short Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters
title_full Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters
title_fullStr Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters
title_full_unstemmed Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters
title_sort evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of cyp3a, oatp, and p-glycoprotein transporters
publisher International Association of Physical Chemists (IAPC)
series ADMET and DMPK
issn 1848-7718
publishDate 2016-10-01
description The metabolic syndrome in HIV infected patients is particularly associated with the use protease inhibitors. Atazanavir is an inhibitor of the cytochrome P 450 (CYP) system, in particular CYP3A4 and CYP2C9 which can affect the metabolism of several drugs. To treat metabolic syndrome in HIV patients repaglinide is used and it is a short acting insulin secretagogues undergoing metabolism with CYP 3A4 and CYP 2C8 enzyme system. The purpose of this study was to assess the possible pharmacokinetic and pharmacodynamic drug interaction of repaglinide and atazanavir in healthy, diabetic and impaired hepatic function rats. Human oral therapeutic doses of atazanavir and repaglinide were extrapolated to rats based on the body surface area. The pharmacokinetic parameters and blood glucose concentrations of repaglinide were determined after oral administration of repaglinide alone (0.5 mg/kg) and in the presence of atazanavir (36 mg/kg) in normal, diabetic and hepatic impaired rats. The pharmacokinetics (PK) and blood glucose concentrations of repaglinide were significantly altered in the presence of atazanavir. The peak plasma concentration (Cmax), area under the plasma concentration time profile (AUC) and elimination half-life of repaglinide were significantly (P<0.0001) increased. The repaglinide clearance (CL) was significantly (P<0.0001) decreased in the presence of atazanavir treatment. In the presence of atazanavir, repaglinide hypoglycaemic activity was increased significantly (P<0.0001) when compared with the repaglinide control group. The present study demonstrated the significant difference in the PK/PD changes due to the enhanced bioavailability and decreased total body clearance of repaglinide may be due to the inhibition of the CYP P450 metabolic system, OATP and P-gp transporters by atazanavir.
topic AIDS
Drug drug interaction
hypoglycaemic activity
Liver dysfunction
Peak plasma concentration Cmax
Area under the curve Auc
Clearance
Elimination half life.
url http://pub.iapchem.org/ojs/index.php/admet/article/view/328
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