Table 3.

Specification of the PK models to determine the pharmacokinetics of the six selected compounds, enalapril, fasudil, amlodipine, prazosin, propranolol and HCTZ to challenge the CVS

Compound	PK model	Literature model	Comments	Species
Enalapril	2-compartmental model with Michaelis-Menten elimination	(Lin et al., 1988)	Data read out from the manuscript and a 2- compartmental model with Michaelis-Menten elimination was optimized in NONMEM	Sprague-Dawley rats
Fasudil	1-compartmental model	(Ikegaki et al., 2001): Non-compartmental analysis	Ka and lag-time were derived from the reported half-life, AUC and Cmax using Berkeley Madonna	Wistar-Kyoto rats
Amlodipine	1-compartmental model	(Stopher et al., 1988): Non-compartmental analysis	Ka was derived from the reported half-life, Vd, F and Tmax using Berkeley Madonna	Sprague-Dawley rats
Prazosin	1-compartmental model	(Hamilton et al., 1985): 1-compartmental model	CL, Vd; scaled to rat using allometric scaling. Ka was estimated	New Zealand white rabbits
Propranolol	3-compartmental model	(van Steeg et al., 2010): 3-compartmental model	Absorption described as an infusion with a fixed duration of 24 h. Ka was estimated	Wistar-Kyoto rats
HCTZ	1-compartmental model	(Asdaq and Inamdar, 2009): 1-compartmental model	Reported: Ke, Ka, Vd, AUC -> F was calculated from these parameters	Wistar-Kyoto rats

The PK models were based on literature models. The adjustments required to account for the differences in experimental conditions and formulations in these literature studies as compared with the experiments described in this paper are described in the ‘Comments’ column.

CL, clearance; F, bioavailability; K_a, absorption rate; K_e, elimination rate; Vd, distribution volume.