Altered pharmacokinetics and pharmacodynamics of repaglinide by ritonavir in rats with healthy, diabetic and impaired hepatic function
-
Thirumaleswara Goud
,
Srinivas Maddi
Abstract
Background: Ritonavir is an antiretroviral drug to treat HIV AIDS and inhibits cytochrome P450 3A4. To treat diabetes mellitus in HIV, repaglinide is coadministered with ritonavir in the clinic. Multiple cytochrome P450 (CYP) isoforms are involved in the metabolism of repaglinide like CYP2C8 and CYP 3A4. In order to predict and understand drug-drug interactions of these two drugs, the pharmacokinetics and pharmacodynamics (PK/PD) of repaglinide and ritonavir were studied in normal, diabetic and hepatic impaired rats. The purpose of the study was to assess the influence of ritonavir on the PK/PD of repaglinide in rats with normal, diabetic and impaired hepatic function.
Methods: Human oral therapeutic doses of ritonavir and repaglinide were extrapolated to rats based on the body surface area. Ritonavir (20 mg/kg, p.o.), alone and along with repaglinide (0.5 mg/kg, p.o.), was given to normal, diabetic and hepatic impaired rats, and the PK/PD were studied.
Results: The pharmacokinetic parameters like peak plasma concentration (Cmax), area under the plasma concentration time profile (AUC) and elimination half life of repaglinide were significantly (p<0.0001) increased when compared to repaglinide control rats. The repaglinide clearance (CL) was significantly (p<0.0001) decreased in the presence of ritonavir treatment. In the presence of ritonavir, repaglinide hypoglycemic activity was increased significantly (p<0.0005) when compared with repaglinide control group.
Conclusions: The significant difference in the PK/PD changes have been due to the increased plasma exposure and decreased total body clearance of repaglinide, which may be due to the inhibition of the CYP P450 metabolic system and organic anion-transporting polypeptide transporter by ritonavir.
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©2016 by De Gruyter
Artikel in diesem Heft
- Frontmatter
- In Memoriam Gérard Siest
- Reviews
- Interethnic variability of pharmacogenetic biomarkers in Mexican healthy volunteers: a report from the RIBEF (Ibero-American Network of Pharmacogenetics and Pharmacogenomics)
- Predictive biomarkers candidates for patients with metastatic colorectal cancer treated with bevacizumab-containing regimen
- Mini Reviews
- The integration and interpretation of pharmacogenomics – a comparative study between the United States of America and Europe: towards better health care
- Investigating the impact of missense mutations in hCES1 by in silico structure-based approaches
- Original Articles
- Lack of genomic diversity in the SLC47A1 gene within the indigenous Xhosa population
- Assessment of cytochrome P450 inhibition and induction potential of lupeol and betulin in rat liver microsomes
- Altered pharmacokinetics and pharmacodynamics of repaglinide by ritonavir in rats with healthy, diabetic and impaired hepatic function
Artikel in diesem Heft
- Frontmatter
- In Memoriam Gérard Siest
- Reviews
- Interethnic variability of pharmacogenetic biomarkers in Mexican healthy volunteers: a report from the RIBEF (Ibero-American Network of Pharmacogenetics and Pharmacogenomics)
- Predictive biomarkers candidates for patients with metastatic colorectal cancer treated with bevacizumab-containing regimen
- Mini Reviews
- The integration and interpretation of pharmacogenomics – a comparative study between the United States of America and Europe: towards better health care
- Investigating the impact of missense mutations in hCES1 by in silico structure-based approaches
- Original Articles
- Lack of genomic diversity in the SLC47A1 gene within the indigenous Xhosa population
- Assessment of cytochrome P450 inhibition and induction potential of lupeol and betulin in rat liver microsomes
- Altered pharmacokinetics and pharmacodynamics of repaglinide by ritonavir in rats with healthy, diabetic and impaired hepatic function
