QP-14

M. M. Posada, K. M. Hillgren, S. D. Hall; Eli Lilly and Company, Indianapolis, IN

BACKGROUND: The potency of secretion inhibitors is determined in vitro as the concentration inhibiting 50% (IC50) of active transport. The ratio of the unbound Cmax (Iu) to the IC50 is used to identify potential clinically relevant inhibitors. Though this metric does not take into account active tubular secretion and glomerular filtration.
METHODS: The proposed mechanistic static model (Equation 1) is based on the well-stirred model. The Clint was scaled up from in vitro transporter clearances or calulated from human data.
RESULTS: The model was tested using substrates and inhibitors of OATs, and predicted decreases in renal clearance within 15% of the observed values.
CONCLUSION: The mechanistic static model accurately predicted the decrease in renal clearance of the OAT substrates by integrating the clearance of filtration and secretion.

Table 1. Observed and predicted clearance ratios of substrates and inhibitors of OATs

Substrates Inhibitors Iu/IC50 Observed Clearance Ratio Predicted Clearance Ratio Observed/ Predicted Reference
Acyclovir Probenecid 5.5 0.71 0.66 1.09 Laskin 1981
Cidofovir Probenecid 5.5 0.61 0.63 0.97 Cundy 1995
Cefaclor Probenecid 8.5 0.48 0.46 1.04 Welling 1979
Cephradine Probenecid 8.5 0.41 0.47 0.87 Welling 1979
Oseltamavir Probenecid 8.5 0.51 0.48 0.94 Hill 2002
Furosemide Probenecid 8.5 0.20 0.21 0.95 Smith 1980
Furosemide Aspirin 0.33 0.84 0.78 1.1 Paterson 2011
Furosemide Diclofenac 0.01 0.99 0.92 0.92 Paterson 2011
Furosemide Naproxen 0.03 0.97 0.92 0.94 Paterson 2011