Table 2.
Summary of glyburide (GLB) drug-dependent parameters
| Parameter | Value | Methods/reference |
|---|---|---|
| Molecular weight | 494.0 | a |
| Log Po:w | 4.79 | b |
| pKa | 5.3 | c |
| B : P ratio | 0.55 | Assumed d |
| fu,p | 0.015 | e |
| Fa | 0.84 | a |
| ka (h−1) | 0.756 | f |
| tlag (h) | 0.39–0.46 | f |
| Fg | 0.91 | Predicted by Qgut model |
| Vss (l kg)−1 | 0.1 | Predictedg |
| CLIV (l h−1) | 4.4 | h |
| CLr (l h−1) | 0.001 | i |
| CLint,CYP (μl min−1/pmol) | CLint,CYP3A4 = 0.238 | j |
| CLint,2C9 = 0.268 | ||
| CLint,CYP2C19 = 0.931 | ||
| CLpd (μl min−1/106 cells) | 24 | Parameter estimationk |
| PSint,OATP2B1 (μl min−1/106 cells) | 43.5 | Parameter estimationk |
| fm | fm,3A = 50% | l |
| fm,2C9 = 30% | ||
| fm,2C19 = 20% |
aReported 32. bhttp://www.drugbank.ca/drugs/DB01016. cLiterature value 68. dThere is no evidence in the literature that glyburide partitions into erythrocytes. Therefore B : P was calculated from the equation: E : P = [B : P − (1 − Hct)]/Hct, where E : P refers to erythrocyte partition coefficient and Hct refers to haematocrit value (mean value of 0.45 used). eAverage of reported value in the literature 5,69. fOptimized in the range of 0.39–0.46 h. The reported value is 0.46 h 70. gPredicted Vss according to Rodgers & Rowland is 0.61 l kg−1 67. This value was further optimized by applying a global Kp scalar of 0.1, in order to match the reported Vss of 0.077 ± 0.013 l kg−1 following i.v. infusion 59. hReported value is 4.4 ± 0.56 l h−1 (n = 8) 59. iReported value 33. jBack calculation from hepatic clearance, fm for individual CYP (see below), and ‘average’ population values for liver weight and hepatic CYP enzyme abundance of 137, 73 and 14 pmol mg−1 protein for CYP3A, 2C9 and 2C19, respectively. Hepatic intrinsic metabolic clearance (= 252.9 l h−1) was predicted using in vitro to in vivo extrapolation. Briefly, in vitro CLint,u determined in HLM 40 was scaled by ‘average’ population values for liver weight and microsomal protein of 1618 g and 38.9 (mg g−1 liver), respectively. Alternatively, in vitro Vmax and Km determined in recombinant CYP enzyme system 34 were scaled by ‘average’ population values for liver weight and respective hepatic CYP enzyme abundance as described above. Both approaches yielded similar values and the mean hepatic intrinsic clearance was used. kHepatic bidirectional permeability clearance (CLpd), and hepatic intrinsic uptake clearance by OATP (or the permeability surface area product, PSint,OATP), were estimated simultaneously using mean glyburide plasma PK data reported in subjects taking a single oral dose of 1.75–5 mg glyburide. lThe contribution from individual CYP obtained using HLM with selective chemical inhibitors is 53%, 28% and 19% for 3A, 2C9 and 2C19, respectively 34. In another study, the contribution from CYP3A was approximately 50%, whereas 2C8 and 2C19 combined contribute 50% 35. However, in vivo drug–drug interaction studies using fluvastatin as the perpetrator (a 2C9 inhibitor) reported AUC % change of 23% 36. In addition, a 2.7-fold higher glyburide AUC in subjects with CYP2C9*1/*3 and CYP2C9*2/*3 vs. CYP2C9*1/*1 was observed 37. This evidence suggests that CYP2C9 plays a significant role in glyburide metabolism in vivo. Therefore, the in vitro contribution from individual CYPs was adjusted accordingly and 50%, 30% and 20% for 3A, 2C9 and 2C19, respectively, was assigned in the final model.