The Pharmacokinetic-pharmacodynamic Assessment of the Hypotensive Effect after Coadministration of Losartan and Hydrochlorothiazide in Spontaneously Hypertensive Rats

The interactive hypotensive effect of the combination treatment of losartan (LOS) and hydrochlorothiazide (HCTZ) was assessed using a pharmacokinetic-pharmacodynamic (PK-PD) model in spontaneously hypertensive rats. Intravenous coadministration of these drugs showed a prolonged and enhanced time-cou...

Full description

Saved in:
Bibliographic Details
Published in:DRUG METABOLISM AND PHARMACOKINETICS 2012, Vol.27 (2), p.207-215
Main Authors: Shimizu, Ryosuke, Miyazaki, Makoto, Iwanaga, Kazunori, Kakemi, Masawo
Format: Article
Language:English
Subjects:
Animals
Antihypertensive Agents - administration & dosage
Drug Therapy, Combination
drug-drug interaction
hydrochlorothiazide
Hydrochlorothiazide - administration & dosage
Hydrochlorothiazide - pharmacokinetics
Hypertension - drug therapy
Hypertension - metabolism
losartan
Losartan - administration & dosage
Losartan - pharmacokinetics
Male
PK-PD model
plasma renin activity
Rats
Rats, Inbred SHR
Treatment Outcome
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The interactive hypotensive effect of the combination treatment of losartan (LOS) and hydrochlorothiazide (HCTZ) was assessed using a pharmacokinetic-pharmacodynamic (PK-PD) model in spontaneously hypertensive rats. Intravenous coadministration of these drugs showed a prolonged and enhanced time-course of the hypotensive effect. A population PK analysis revealed the delayed elimination of LOS after coadministration. The time-course of the plasma renin activity (PRA) was measured, and showed a more continuative time profile after coadministration compared with the administration of LOS alone. An indirect response model was applied to describe the relationship between the PK of LOS and the PRA profile, and the Emax value for the increase of the PRA by LOS was increased with the dose of HCTZ. Blood pressure was linked to the PRA through an effect compartment. The model successfully described the relationship between the doses of LOS and HCTZ and their interactive hypotensive effect. These results indicate that the interaction for blood pressure in the combination treatment of LOS and HCTZ can be estimated using the doses of the drugs and the PRA-mediated PK-PD model.
ISSN:1347-4367
1880-0920
DOI:10.2133/dmpk.DMPK-11-RG-060