Is urethane–chloralose anaesthesia appropriate for pharmacokinetic–pharmacodynamic assessment? Studies with carvedilol

Naunyn-Schmiedeberg's Arch Pharmacol

Polizio

et al. 2011

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The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5 mg kg(-1) (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic-pharmacodynamic (PK-PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1 mg kg(-1) compared with WKY rats. PK-PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (E (max), -27.6 ± 3.9%; p < 0.05) compared with WKY group (E (max), -13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E (max), -45.5 ± 5.0%; p < 0.05) with regard to WKY group (E (max), -17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.

Section: Pharmacokinetic-pharmacodynamic Analysismentioning

confidence: 93%

Enantioselective pharmacokinetic and pharmacodynamic properties of carvedilol in spontaneously hypertensive rats: focus on blood pressure variability

Naunyn-Schmiedeberg's Arch Pharmacol

Polizio

et al. 2011

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“…The chronotropic and blood pressure lowering effect of carvedilol have been studied in normotensive and NG-nitro-L-arginine methyl ester (L-NAME) hypertensive rats when they are awake or after intravenous anesthesia with urethane--chloralose [74]. Plasma carvedilol concentrations and changes in heart rate and blood pressure were continuously monitored.…”

Section: Preclinical Pk/pd Models Of B-blockersmentioning

confidence: 99%

“…Plasma carvedilol concentrations and changes in heart rate and blood pressure were continuously monitored. PK/PD parameters of carvedilol in both conditions were evaluated using an effectcompartment model [74]. Although anesthesia did not influence carvedilol concentration producing 50% of heart rate and blood pressure reduction, the use of urethane--chloralose increased maximal chronotropic and hypotensive response induced by the b-blocker [74].…”

Section: Preclinical Pk/pd Models Of B-blockersmentioning

confidence: 99%

Models for evaluating the pharmacokinetics and pharmacodynamics for β-blockers

Höcht

Expert Opinion on Drug Metabolism & Toxicology

et al. 2014

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PK models and PK/PD modeling have clearly contributed to characterization of the PK and PD properties of β-blockers. Differences in cardiovascular actions between classical β-blockers and vasodilatory β-blockers need to be further studied in order to confirm the clinical benefits of the new-generation of β-blockers. PK/PD modeling may contribute to clarify the importance of heterogeneity of PK and PD properties of β-blockers potentially improving the selection of the adequate agent and dose regimen in the treatment of cardiovascular diseases.

“…As anesthesia could modify animal physiology introducing artifacts in pharmacological studies [40], the impact of anesthetic drugs used and their dosage must be taken into account during PK/PD modeling. A PK/PD study has evaluated the impact of urethane-chloralose anesthesia on PK/PD properties of carvedilol in control rats and NG-nitro-L-arginine methyl ester (L-NAME) hypertensive animals [41]. By using an effect compartment PK/PD model, it was found that urethane-chloralose did not modify PK properties and potency of the chronotropic and hypotensive effect of carvedilol, but significantly enhanced E max estimation when compared with awake animals [41].…”

mentioning

confidence: 99%

“…A PK/PD study has evaluated the impact of urethane-chloralose anesthesia on PK/PD properties of carvedilol in control rats and NG-nitro-L-arginine methyl ester (L-NAME) hypertensive animals [41]. By using an effect compartment PK/PD model, it was found that urethane-chloralose did not modify PK properties and potency of the chronotropic and hypotensive effect of carvedilol, but significantly enhanced E max estimation when compared with awake animals [41]. These results suggest the need to validate anesthetic drugs for accurate PK/PD modeling of β-blockers in preclinical studies.…”

mentioning

confidence: 99%

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

Höcht

et al. 2016

Int. J. Pharmacokinet.

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Review β-blockers play a central role in the treatment of the various main cardiovascular diseases, including hypertension, coronary artery disease and systolic heart failure. As a therapeutic class, β-blockers form a heterogeneous family that differs in their pharmacokinetic (PK) and pharmacodynamic (PD) properties, highlighting the relevance of the extensive evaluation of PK/PD properties of these agents in order to optimize the outcomes of the treatment of cardiovascular diseases. Preclinical and clinical studies using PK/PD models have been able to identify different factors associated with cardiovascular response of β-blockers, including age, pharmaceutical formulation and genetic polymorphism, among others. PK/PD modeling of β-blockers can also be attractive for the early detection of poor responders and the optimization of dose regimen in their different indications.