Relative contribution of paracellular and transcellular transport to overall transport of metformin as a function of donor concentration in Caco-2 cells
Metformin Concentration | Experimental | Metformin Model Prediction | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mannitol Papp, totala | Metformin Papp, totala | Papp, total
b
| Papp, trans
c
| Papp, para
c
| Transcellulard | Paracellulard | ||||||
| cm/s × 10–7 | cm/s × 10–7 | % | ||||||||||
| 0.05 mM | 5.4 ± 1.7 | 5.0 ± 0.57 | 4.9 | 0.4 | 4.5 | 9 | 91 | |||||
| 0.5 mM | 5.1 ± 0.9 | 3.9 ± 0.56 | 4.3 | 0.3 | 4.0 | 7 | 93 | |||||
| 10 mM | 5.4 ± 0.9 | 1.4 ± 0.24 | 1.3 | 0.1 | 1.3 | 5 | 95 | |||||
| 0.05 mM+ quinidinee | 5.9 ± 1.3 | 1.7 ± 0.15 | 1.9 | 0.1 | 1.8 | 3 | 97 | |||||
| Control | 5.8 ± 0.7 |
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↵ a Determined from AP to BL transport of [14C]mannitol in the presence of varying concentrations of unlabeled metformin over 90 min transport experiment. Control value equals mannitol flux in the absence of metformin or quinidine. Data represent mean ± S.D.; n = 3
↵ b Determined from the model prediction of total metformin transported as a function of time
↵ c Determined from simulation of the amount of metformin transported as a function of time using a subset of the overall kinetic model incorporating solely paracellular or transcellular transport
↵ d Determined from the predicted paracellular or transcellular permeability as a percentage of the total predicted permeability
↵ e Metformin (0.05 mM) transport and model predictions in the presence of quinidine (0.2 mM) in the AP donor compartment