Article

Pharmacokinetic-pharmacodynamic modeling of the effect of fluvoxamine on p-chloroamphetamine-induced behavior.

Department of Drug Metabolism and Pharmacokinetics, Johnson and Johnson Pharmaceutical Research and Development, a Division of Janssen Pharmaceutica N.V., Beerse, Belgium.
European Journal of Pharmaceutical Sciences (impact factor: 3.21). 11/2007; 32(3):200-8. DOI:10.1016/j.ejps.2007.07.004 pp.200-8
Source: PubMed

ABSTRACT The pharmacokinetic-pharmacodynamic (PK-PD) correlation of the effect of fluvoxamine on para-chloroamphetamine (PCA)-induced behavior was determined in the rat. Rats (n=66) with permanent arterial and venous cannulas received a 30-min intravenous infusion of 1.0, 3.7 or 7.3 mg kg(-1) fluvoxamine. At various time points after the start of fluvoxamine administration, a single dose of PCA (2.5 mg kg(-1)) was injected in the tail vein and resulting behavioral effects, excitation (EXC), flat body posture (FBP) and forepaw trampling (FT), were immediately scored (scores: 0, 1, 2 or 3) over a period of 5 min. In each individual animal the time course of the fluvoxamine plasma concentration was determined up to the time of PCA administration. Observed behavioral effects were related to fluvoxamine plasma concentrations. Fluvoxamine pharmacokinetics was described by a population three-compartment pharmacokinetic model. The effects of fluvoxamine on PCA-induced behavior (probability of EXC, FBP and FT) were directly related to fluvoxamine plasma concentration on the basis of the proportional odds model. For EXC, EC(50) values for the cumulative probabilities P(Y<1), P(Y<2), P(Y<3) were 237+/-39, 174+/-28 and 100+/-20 ng ml(-1), respectively. Slightly higher EC(50) values were obtained for the corresponding effects on FBP and FT. This investigation demonstrates the feasibility of PK-PD modeling of categorical drug effects in animal behavioral pharmacology. This constitutes a basis for the future development of a mechanism-based PK-PD model for fluvoxamine in this paradigm.

0 0
 · 
0 Bookmarks
 · 
21 Views
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Full-text

View
0 Downloads
Available from

Keywords

animal behavioral pharmacology
 
cumulative probabilities P(Y<1)
 
flat body posture
 
fluvoxamine administration
 
Fluvoxamine pharmacokinetics
 
fluvoxamine plasma concentrations
 
future development
 
individual animal
 
mechanism-based PK-PD model
 
Observed behavioral effects
 
PCA administration
 
PCA-induced behavior
 
permanent arterial
 
PK-PD modeling
 
population three-compartment pharmacokinetic model
 
proportional odds model
 
single dose
 
time course
 
various time points
 
venous cannulas