Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data

  • Agnès Poirier
  • Anne-Christine Cascais
  • Christoph Funk
  • Thierry Lavé


The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro data in order to refine the PBPK model. The model could then be applied to human in vitro uptake transport data using valsartan as a probe substrate. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. The uptake rate of valsartan was higher for rat hepatocytes (K m,u = 28.4 ± 3.7 μM, V max = 1318 ± 176 pmol/mg/min and P dif = 1.21 ± 0.42 μl/mg/min) compared to human hepatocytes (K m,u = 44.4 ± 14.6 μM, V max = 304 ± 85 pmol/mg/min and P dif = 0.724 ± 0.271 μl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration–time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CLP) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds.


PBPK Transporters Liver Uptake Hepatocytes Valsartan 


CLP (ml/min/kg)

Plasma clearance

CLHP (ml/min/kg)

Plasma hepatic clearance \( {\text{CL}}_{\text{HP}} = {\text{CL}}_{\text{P}} \times f_{\text{bile}} \)

CLRP (ml/min/kg)

Plasma renal clearance \( {\text{CL}}_{\text{RP}} = {\text{CL}}_{\text{P}} \times fe \)


Enterohepatic recirculation


Fraction of the dose excreted unchanged in bile


Fraction of the dose excreted unchanged in urine


Fraction unbound in plasma


Hepatocytes per gram of liver

Km,u (μM)

Michaelis–Menten affinity constant unbound (I influx, E efflux)


mg of total protein per million hepatocytes

mw (g/mol)

Molecular weight


Organic anion transporting peptide


Physiologically based pharmacokinetic

Pdif (μl/min/mg)

Passive diffusion at the basolateral membrane determined in vitro (through CHO cells membrane \( \_{\text{CHO}} \) or human hepatocytes membrane \( \_{\text{HH}} \))


Relative activity factor


Blood-plasma ratio

Vmax (pmol/min/mg)

Michaelis–Menten maximum velocity (I influx, E efflux)

In vitro mechanistic model

Cint (μM)

Compound concentration in intracellular space in vitro

Cex (μM)

Compound concentration in the medium in vitro


Fraction non-specifically bound in the in vitro system

Vint (μl)

Intracellular volume of all cells in one well

Vex (μl)

Volume of the incubation medium in vitro

Whole PBPK model

Cbi (μg/ml)

Blood concentration in (arterial) of tissue

Cbo (μg/ml)

Blood concentration out (venous) of tissue

Ce (μg/ml)

Drug concentration in extracellular space (u = unbound) in vivo

Ct (μg/ml)

Drug concentration in intracellular space (u = unbound) in vivo


Fraction unbound in the in vitro incubation


Fraction unbound in liver



Jmax (mg/s)

Michaelis–Menten maximum velocity scaled to in vivo (I influx, E efflux)


Partition coefficient


Partition coefficient in extracellular space (L: in liver = in Disse space)

Mbile (μg)

Amount of drug cleared by biliary excretion

PSTC (ml/s)

Permeability-surface area product at the basolateral membrane

PSTCAp (ml/s)

Permeability-surface area product at the apical membrane

QL (ml/min/kg)

Liver blood flow

Ve (ml)

Extracellular volume fraction of tissue

VP (ml)

Plasma volume


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Agnès Poirier
    • 1
  • Anne-Christine Cascais
    • 1
  • Christoph Funk
    • 1
  • Thierry Lavé
    • 1
  1. 1.Non-Clinical Development-Drug SafetyF. Hoffmann-La Roche Ltd.BaselSwitzerland

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