TABLE 5.
Multivariable analysis of CYP1A2, CYP2C9, CYP2C19, and CYP3A activities
| CYP450 isoform | Covariates | Parameter estimate (β) ± SE | p value | Adjusted R 2 |
|---|---|---|---|---|
| CYP2C19 (log 5‐OH‐omeprazole/omeprazole) | BMI (kg/m2) | −0.000 ± 0.013 | 0.99 | 0.43 |
| T2DM (yes) | −0.64 ± 0.26 | 0.016 | ||
| NAFLD (yes) | −0.63 ± 0.25 | 0.015 | ||
| CYP3A (MDZ absolute bioavailability, %) | BMI (kg/m2) | 0.030 ± 0.009 | 0.0011 | 0.19 |
| T2DM (yes) | 0.40 ± 0.18 | 0.033 | ||
| NAFLD (yes) | −0.027 ± 0.18 | 0.88 | ||
| CYP3A (MDZ systemic clearance, L/h) | BMI (kg/m2) | 0.015 ± 0.007 | 0.041 | 0.06 |
| T2DM (yes) | 0.11 ± 0.15 | 0.46 | ||
| NAFLD (yes) | −0.027 ± 0.15 | 0.86 | ||
| CYP3A (log 4βOHC, ng/ml) | BMI (kg/m2) | −0.020 ± 0.006 | 0.0017 | 0.25 |
| T2DM (yes) | −0.012 ± 0.12 | 0.92 | ||
| NAFLD (yes) | −0.27 ± 0.12 | 0.029 | ||
| CYP1A2 (log paraxanthine/caffeine) | BMI (kg/m2) | −0.007 ± 0.005 | 0.21 | 0.10 |
| T2DM (yes) | 0.14 ± 0.11 | 0.20 | ||
| NAFLD (yes) | −0.14 ± 0.11 | 0.19 | ||
| Log TNF‐α (pg/ml) | 0.074 ± 0.034 | 0.032 | ||
| CYP2C9 (log losartan/LCA) | BMI (kg/m2) | −0.001 ± 0.006 | 0.89 | 0.48 |
| T2DM (yes) | 0.013 ± 0.12 | 0.92 | ||
| NAFLD (yes) | −0.24 ± 0.12 | 0.050 | ||
| Log TNF‐α (pg/ml) | 0.081 ± 0.038 | 0.037 |
Note: The models were adjusted for age, sex (male/female), and genotype‐predicted‐phenotype (categorized according to Table 2: CYP2C19: *1/*1 (normal), *17/*17 or *1/*17 (ultrarapid/rapid), *1/*2 or *2/*17 (intermediate), and *2/*2 or *2/*4 (poor); CYP3A4: *1/*1 (normal) and *1/*22 (intermediate); CYP3A5: *1/*3 (intermediate) and *3/*3 (poor); CYP1A2: *1/*1 or *1/*1F (normal) and *1F/*1F (hyperinducer); CYP2C9: *1/*1 or *1/*2 (normal), *1/*3 or *2/*2 (intermediate), and *3/*3 (poor)).
Abbreviations: 4βOHC, 4β‐hydroxycholesterol; 5‐OH‐omeprazole, 5‐hydroxyomeprazole; BMI, body mass index; CYP, cytochrome P450; LCA, losartan carboxylic acid; MDZ, midazolam; NAFLD, nonalcoholic fatty liver disease; TNF‐α, tumor necrosis factor‐α; T2DM, type 2 diabetes mellitus.