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PKPD modelling of the interrelationship between mean arterial BP , cardiac output and total peripheral resistance in conscious rats
Author(s) -
Snelder N,
Ploeger B A,
Luttringer O,
Rigel D F,
Webb R L,
Feldman D,
Fu F,
Beil M,
Jin L,
Stanski D R,
Danhof M
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12190
Subject(s) - hydrochlorothiazide , medicine , enalapril , pharmacology , drug , prazosin , pharmacokinetics , blood pressure , cardiology , antagonist , angiotensin converting enzyme , receptor
Background and Purpose The homeostatic control of arterial BP is well understood with changes in BP resulting from changes in cardiac output ( CO ) and/or total peripheral resistance ( TPR ). A mechanism‐based and quantitative analysis of drug effects on this interrelationship could provide a basis for the prediction of drug effects on BP . Hence, we aimed to develop a mechanism‐based pharmacokinetic‐pharmacodynamic (PKPD) model in rats that could be used to characterize the effects of cardiovascular drugs with different mechanisms of action ( MoA ) on the interrelationship between BP , CO and TPR . Experimental Approach The cardiovascular effects of six drugs with diverse MoA , (amlodipine, fasudil, enalapril, propranolol, hydrochlorothiazide and prazosin) were characterized in spontaneously hypertensive rats. The rats were chronically instrumented with ascending aortic flow probes and/or aortic catheters/radiotransmitters for continuous recording of CO and/or BP . Data were analysed in conjunction with independent information on the time course of drug concentration using a mechanism‐based PKPD modelling approach. Key Results By simultaneous analysis of the effects of six different compounds, the dynamics of the interrelationship between BP , CO and TPR were quantified. System‐specific parameters could be distinguished from drug‐specific parameters indicating that the model developed is drug‐independent. Conclusions and Implications A system‐specific model characterizing the interrelationship between BP , CO and TPR was obtained, which can be used to quantify and predict the cardiovascular effects of a drug and to elucidate the MoA for novel compounds. Ultimately, the proposed PKPD model could be used to predict the effects of a particular drug on BP in humans based on preclinical data.