Table 2.
Pharmacokinetic parameters of verapamil and furosemide for PBPK simulation in diabetic rats (DM) and control rats (CON).
| Parameter | Unit | Furosemide | Verapamil | ||
|---|---|---|---|---|---|
| CON rats | DM rats | CON rats | DM rats | ||
| Vc | L/kg | 0.127 [148] | 0.127 | 0.505 a | 0.505 |
| k21 | h−1 | 0.835 [148] | 0.835 | 11.880 a | 11.88 |
| k12 | h−1 | 0.989 [148] | 0.989 | 10.740 a | 10.74 |
| fu | % | 10.4 [105] | 10.4 [89] | 0.05 [93] | 0.05 |
| Kt:p | Liver | 0.33 [148] | 0.33 | 8.20 b | 8.20 |
| Kt:p | Intestine | 0.517 [148] | 0.517 | 319.39 b | 319.39 |
| Kt:p | Kidney | 1.36 [148] | 1.36 | / | / |
| Papp,A-B (caco-2) | cm/s × 10−6 | 6.90 [149] | 3.45 c | 13.8 | 13.8 |
| Papp,B-A (caco-2) | cm/s × 10−6 | / | / | 24.84 | 14.90 d |
| CLkidney | mL/min/kg | 4.33 [105] | / | ||
| CLliver | mL/min/kg | 2.20 [105] | / | ||
| Fu × CLint,liver | mL/min/250 g | 0.60 e | 0.75 f | / | / |
| Fu × CLint,kidney | mL/min/250 g | 1.19 e | 0.48 g | / | / |
| Microsomes | |||||
| Liver | |||||
| Vmax | nmol/(min/mg prot) | / | / | 1.60 [27] | 2.38 [27] |
| Km | μM | / | / | 13.21 [27] | 16.09 [27] |
| Intestine | |||||
| Vmax | pmol/(min/mg prot) | / | / | 49.04 [27] | 22.70 [27] |
| Km | μM | / | / | 34.06 [27] | 55.37 [27] |
a Estimated using the reported data [150]; b estimated according to a method [151] reported by Ruark et al. and physicochemical properties of verapamil; c function of intestinal MCT6 was set to be 50% that of control rats [47]; d level of intestinal P-gp protein was 60% that of control rats [82]; e fu × Clint were estimated using equation fu*Clint = Q × CL/(Q − CL); f contribution of CYP2C11 was 61.5% of the total metabolism [152], rests (38.5%) were assumed to attributed to CYP2E1 and CYP3As. Diabetes increased the expression of CYP2E1 and CYP3As by 3-fold [28] and expression of CYP2C11 mRNA was decreased to 16% that of control rats [47]; g function of renal OATs was decreased to 40% that of control rats [115].