Table 2.
Physiological, experimental, and final calculated parameters for PBPK models of caffeine and paraxanthine established in this study
| Parameter | Caffeine | Paraxanthine |
|---|---|---|
| Model input parameters | ||
| Molecular weight | 194 | 180 |
| Octanol–water partition coefficient | −0.04 | −0.279 |
| Plasma unbound fraction | 0.758 | 0.798 |
| Blood–plasma concentration ratio | 0.822 | 0.798 |
| Liver–plasma concentration ratio | 0.681 | 0.689 |
| Fraction absorbed × intestinal availability | 1 | – |
| Absorption rate constant, 1/h | 4.94 ± 0.15 a | – |
| Volume of systemic circulation, L | 18.8 ± 0.1 a | 74.5 ± 0.1 a |
| Hepatic intrinsic clearance, L/h | 2.70 ± 0.05 a | 6.66 ± 0.08 a |
| Hepatic clearance, L/h | 2.00 | 5.04 |
| Renal clearance, L/h | 0.06 | 0.15 |
| Estimated values b | ||
| Cmax in plasma, ng/mL | 5340 (1.3) c | 649 (0.45) c |
| AUC in plasma, ng h/mL | 29,300 (1.1) c | 3440 (0.40) c |
| Reported levels d | ||
| Cmax in plasma, ng/mL | 4020 | 1450 |
| AUC in plasma, ng h/mL | 26,600 | 8680 |
| Bioavailability | 1 | – |
| Urinary excretion of unchanged drug | 0.03 | – |
The plasma unbound fraction, octanol–water partition coefficient, blood-to-plasma concentration ratio, and liver-to-plasma concentration ratio of caffeine and paraxanthine were estimated using in silico tools [23]
aData are means ± standard deviations by fitting to measured concentrations
bValues estimated by the simplified PBPK models for a normal single oral dose of 100 mg caffeine
cValues in parentheses are ratios to the reported/observed values taken from the literature [3]
dReported values for four Japanese male volunteers administered single oral doses of 100 mg caffeine [3]