IN VITRO–IN VIVO SCALE-UP OF DRUG TRANSPORT ACTIVITIES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 571

analyses are required to investigate the in vitro-in vivo correlation of efflux transport
in the kidney. Regarding the reabsorption process, we can qualitatively demonstrate
the involvement of reabsorption in the renal clearance by observing the reduction in the
reabsorption by diuresis induced by mannitol. 52 However, there is no appropriate in
vitro experimental system for the quantitative prediction of transport activity involving
reabsorption.

19.5. PREDICTION OF BLOOD-BRAIN BARRIER AND BLOOD-CSF
BARRIER TRANSPORT FROM IN VITRO DATA

There are many transporters on the BBB and BCSFB that strictly regulate the entry
of xenobiotics into the brain. In general, a change in the transport activity in BBB
and BCSFB does not affect the body clearance and time profiles of the plasma con-
centration, but markedly affects the brain distribution, so it is difficult to predict the
function of transporters in BBB and BCSFB from the in vivo pharmacokinetics of
drugs, and several methods to assess the drug permeability into the brain have been
created. 53 The role of Pgp in the brain disposition of drugs has been studied most
extensively. Adachi et al. have investigated whether the in vivo brain distribution
in mdr1a/1b knockout and normal mice can be predicted from in vitro transcellu-
lar transport studies using MDR1-expressing LLC-PK1 cells. 54 As shown in Fig-
ure 19.7 a , apical-to-basal and basal-to-apical flux across the cell monolayer can be
described by

PS b , eff
PS a , eff +

PS a - to - b = PS a , inf (14)

PS b , eff

PS a , eff
PS a , eff +

PS b - to - a = PS b , inf (15)

PS b , eff

where PS a , inf and PS a , eff represent the influx clearance from the apical compartment
to the cells and the efflux clearance from cells to the apical compartment, respectively,
and PS b , inf and PS b , eff represent the influx clearance and efflux clearance across the
basal membrane. The flux ratio (PS b - to - a /PS a - to - b ) in MDR1-expressing LLC-PK1
cells can be calculated as

PS b , inf (PS a , eff + PS Pgp )

PS a , inf PS b , eff

flux ratio = (16)

Also, the corrected flux ratio is defined as the ratio of the flux ratio in MDR1-
expressing LLC-PK1 cells to that in parent LLC-PK1 cells:

PS Pgp
PS a , eff

corrected flux ratio = 1 + (17)