Table 2.
Specification of the PK models to describe the pharmacokinetics of the effects of the six compounds selected, enalapril, fasudil, amlodipine, prazosin, propranolol and HCTZ, on the CVS
| Compound | PK model | Literature model | Comments | Species |
|---|---|---|---|---|
| Amiloride | Two-compartmental model with liver compartment | (Segre et al., 1998) Two-compartmental model with liver compartment | – | Wistar rats |
| Amlodipine | One-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 |
| Atropine | Two-compartmental model | (Perlstein et al., 2002) Two-compartmental model | Ka was estimated simultaneously with PD | Sabra rats |
| Enalapril | Two-compartmental model with Michaelis-Menten elimination | (Lin et al., 1988) and (Li et al., 2007) | Data read out from the manuscripts and a two- compartmental model with Michaelis-Menten elimination was optimized in NONMEM | Sprague-Dawley rats |
| Fasudil | One-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 | WKY rats |
| HCTZ | One-compartmental model | (Asdaq and Inamdar, 2009): One-compartmental model | Reported: Ke, Ka, Vd, AUC/F was calculated from these parameters | WKY rats |
| Prazosin | One-compartmental model | (Hamilton et al., 1985): one-compartmental model | CL, Vd; scaled to rat using allometric scaling. Ka was estimated | New Zealand white rabbits |
| Propranolol | Three-compartmental model | (van Steeg et al., 2010) and (Belpaire et al., 1990): three-compartmental model | Distribution and elimination parameters were fixed to van Steeg et al. Ka was estimated in NONMEM using data obtained from Belpaire et al. | WKY 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; Ka, absorption rate; Ke, elimination rate; Vd, distribution volume.