Document Detail

The pharmacokinetic-pharmacodynamic assessment of the hypotensive effect after coadministration of losartan and hydrochlorothiazide in spontaneously hypertensive rats.
MedLine Citation:
PMID:  22076447     Owner:  NLM     Status:  Publisher    
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 E(max) 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.
Ryosuke Shimizu; Makoto Miyazaki; Kazunori Iwanaga; Masawo Kakemi
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-10
Journal Detail:
Title:  Drug metabolism and pharmacokinetics     Volume:  -     ISSN:  1880-0920     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101164773     Medline TA:  Drug Metab Pharmacokinet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Shionogi & Co., Ltd., Drug Developmental Research Laboratories, Drug Metabolism & Pharmacokinetics.
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