Summary of THEO drug-dependent parameters
| Parameter | Value | Methods/Reference |
|---|---|---|
| Molecular weight | 180.2 | Librarya |
| Log Po:w | −0.02 | Library |
| pKa | 8.8,0.99 | Library |
| B/P ratio | 0.815 | Library |
| fu,p | 0.58 | b |
| Fa | 0.97 | Predicted c |
| ka (h−1) | 0.154(SR), 1.98(IR) | Predicted d |
| Fg | 1 | Predicted by Qgut e |
| Vss (l/kg) | 0.39 | Predicted f |
| CLIV (l/h) | 3.0 | g |
| CLr (l/h) | 0.45 | h |
| CLint,u (l/hr) | 4.6 | i |
| fm and fe (%) | J | |
| fm,1A2 | 68 | |
| fm,3A | 7 | |
| fm,2E1 | 10 | |
| fe | 15 |
Qgut, hybrid parameter of blood flow and drug permeability; Vss, volume of distribution at steady state.
↵a Refers to Simcyp compound library (version 11.1).
↵b Reported value is in the range of 0.56–0.60 (Hendeles et al., 1985; St-Pierre et al., 1985), and the mean value was used.
↵c Predicted from Caco-2 permeability of 25*10−6 cm/s (library) in Simcyp (version 11.1).
↵d IR (immediate release): predicted from Caco-2 permeability of 25*10−6 cm/s (library) in Simcyp (version 11.1). SR (sustained release): estimated from reported t1/2,a (absorption half-life) (Hendeles and Weinberger, 1983).
↵e Qgut model is provided in the Simcyp simulator. It retains the form of the “well stirred” liver model, but the flow term (Qgut) is a hybrid of both permeability through the enterocyte membrane and villous blood flow (Yang et al., 2007).
↵f Predicted according to Rodgers and Rowland (2007).
↵g Reported CLIV in nonpregnant, nonsmokers is 3.0 ± 0.7 l/h (number of studies = 26) (University of Washington Drug Interaction Database, http://www.druginteractioninfo.org/).
↵h Calculated by taking the product of CLIV and reported mean fe . Reported fe ranges 13–18% (n = 22) in nonpregnant, nonsmoking healthy volunteers (Tang-Liu et al., 1982; St-Pierre et al., 1985) and 16.0% ± 3.3% (n = 5) in postpartum women (Frederiksen et al., 1986) following i.v. dosing. Weighted mean fe was used.
↵i Back calculation from well stirred liver model using QH,B (hepatic blood flow) of 90 l/h.
l The contribution from individual CYP obtained in vitro is 91.7, 8, and 0.06% for 1A2, 2E1, and 3A, respectively (Tjia et al., 1996). However, in vivo drug-drug interaction studies using diltiazem and verapamil as the perpetrators (both are CYP3A mechanism-based inhibitors) reported an AUC percent change of 12–18% (Sirmans et al., 1988; Stringer et al., 1992), suggesting that CYP3A played a greater role in THEO metabolism in vivo. Therefore, the contribution from individual CYP (80, 8, and 12% for 1A2, 2E1, and 3A, respectively) was adjusted accordingly. In vivo fm for individual P450 was calculated by taking the product of fm (1 − fe) and the contribution from individual P450.