Comparison of in vivo pharmacokinetic data with values predicted from in vitro liver microsomal intrinsic clearance data
| Rat | Guinea Pig | Dog | Monkey | Human | |
|---|---|---|---|---|---|
| CL′int(ml/min/mg microsomal protein)4-a | 0.248 | 0.389 | 0.021 | 2.54 | 0.0077 |
| CL′int(ml/min/kg)4-b | 446 | 700 | 30 | 3658 | 6.9 |
| fu(blood) 4-c | 0.0083 | 0.0087 | 0.0082 | 0.0049 | 0.044 |
| fu(microsomes) 4-d | 0.031 | 0.040 | 0.010 | 0.027 | 0.033 |
| CLh (predicted, ml/min/kg)4-e | |||||
| Well Stirred Model: | |||||
| fu(microsomes) included | 44 | 48 | 14 | 41 | 6.3 |
| fu(microsomes)disregarded | 3.5 | 5.6 | 0.2 | 13 | 0.3 |
| Parallel Tube Model: | |||||
| fu(microsomes)included | 57 | 62 | 18 | 44 | 7.4 |
| fu(microsomes)disregarded | 3.6 | 5.8 | 0.2 | 15 | 0.3 |
| CLbl (actual, ml/min/kg)4-f | 45 | 107 | 25 | 39 | <84-g |
| Fh (predicted, %)4-e | |||||
| Well Stirred Model: | |||||
| fu(microsomes)included | 37 | 32 | 59 | 6.2 | 69 |
| fu(microsomes)disregarded | 95 | 92 | 99 | 71 | 99 |
| Parallel Tube Model: | |||||
| fu(microsomes)included | 18 | 11 | 50 | <0.1 | 63 |
| fu(microsomes)disregarded | 95 | 92 | 99 | 67 | 99 |
| F (actual, %)4-f | 15 | <0.2 | 28 | 2.1 | ≈604-g |
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↵4-a In vitro intrinsic clearance data from Table1.
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↵4-b Calculated using standard values of 45 mg of microsomal protein/g liver for all species and the following values for g liver/kg body weight: rat, 40; guinea pig, 40; dog, 32; monkey, 32; and human, 20.
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↵4-c Calculated from protein binding and blood-to-plasma ratios from Reed-Hagen et al., (2000).
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↵4-d Determined using equilibrium dialysis at microsomal protein concentrations used in substrate saturation experiments and ezlopitant concentrations atKMapp, by the method described in Obach (1997).
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↵4-e Values calculated using the following equations: Well Stirred Model; fu(microsomes) included:
Well Stirred Model; fu(microsomes) disregarded:
Parallel Tube Model; fu(microsomes) included:
Parallel Tube Model: fu(microsomes) disregarded:
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↵4-f Data from Reed-Hagen et al., (2000).
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↵4-g Intravenous data for human is unavailable. Clearance calculated after oral administration is approximately 8 ml/min/kg, and as such represents an upper limit for intravenous clearance in the case that ezlopitant is completely absorbed after oral administration. Estimation of 60% oral bioavailability is based on F = 1 − (CL/Q). As such, this value would represent an upper estimate assuming complete oral absorption.
