IN VITRO–IN VIVO SCALE-UP OF DRUG TRANSPORT ACTIVITIES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 570

2

1.5

1

0.5

0

0 0.5 1 1.5 2

Value predicted
(mL/min . g kidney)

FIGURE 19.6. Relationship between the values observed and predicted for renal uptake clear-
ance mediated by rat Oat1 and Oat3. The values predicted represent the sum of the rat Oat1- and
Oat3-mediated uptake corrected by the relative transport activity of the test compounds with
the reference compounds (PAH for Oat1 and pravastatin for Oat3). Each symbol represents
an individual substrate. (From ref. 49, with the kind permission of the American Society for
Pharmacology and Experimental Therapeutics.)

RAF method using PAH and pravastatin as reference compounds, and investigated
the inhibitory effects of PAH, PCG, and pravastatin on their uptake in rat kidney
slices. They concluded that OAT3 accounts primarily for CMPF uptake and OAT1 for
IA and HA uptake, whereas OAT1 and OAT3 contribute almost equally to the renal
uptake of IS.
To predict the uptake clearance in human kidney directly from in vitro analyses,
Nozaki et al. characterized the transport properties of compounds by using human
kidney slices prepared from the normal parts of a kidney carcinoma removed during
surgery. 91 Regarding the efflux transporters in the kidney, some candidate transporters
have been characterized, but it is still unclear which transporters are responsible for
renal efflux transport. Hasegawa et al. have found that the basal-to-apical transcellular
transport of some Oat ligands across the LLC-PK1 cell monolayer was enhanced by
the transfection of rat Oat1 or Oat3, suggesting that LLC-PK1 cells express the
efflux transporters endogenously (Hasegawa et al., submitted). They also found that
substitution of Na + ions by K + ions in the incubation medium resulted in a reduction
in the transcellular clearance and that the extent of this reduction depended on the
substrates, implying that both voltage-dependent and voltage-independent systems
are involved in the efflux of substrates in LLC-PK1 cells. They then excluded the
involvement of urate transporter (UAT) in the PAH efflux, due to the fact that they
found no inhibition of its transport by pyrazinoic acid and transfection of siRNA and
suggested that MRP4 contributes partially to its efflux in LLC-PK1 cells since MRP4
siRNA reduced its transcellular transport. Brush border membrane vesicles (BBMVs)
are also useful tools for the characterization of efflux transport systems, 51 but further