where FR,fu, GFR, and CLsecare the reabsorbed fraction, protein unbound
fraction in the blood, glomerular filtration rate and secretion rate, respectively.
GFR is a passive process by which only unbound drugs can be filtered, whereas
reabsorption and secretion often involve active transporters. Technically, it is
difficult to quantify each process of renal excretion. However, the excretion ratio
(ER, which is the CLR/(fuGFR) ratio) reflects the relative contribution of each
process to the overall renal excretion. If the ER of the drug is greater than unity,
the tubular secretion is more dominant. In contrast, when the ER is less than
unity, tubular reabsorption is more significant.
Uptake transporter knockout mice, such as Oat(-/-), Oct(-/-), and Pept2(-/-)
mice, have been available to evaluate the role of these transporters in renal
clearance of selected substrates. In the kidney, basolaterally localized OAT1-3
and OCT1-2 (Fig. 6.1d) are important for renal tubular secretion. OAT4 and
PEPT1-2 localized in the brush-border membrane are mainly responsible for
renal reabsorption. After IV administration of½^14 Cglycylsarcosine (GlySar)
(0.05mmol/g of body weight) to wild type and Pept2(-/-) mice, both total and
renal clearance of GlySar increased two fold in Pept2(-/-) mice, resulting in
concomitantly lower systemic concentrations compared to wild type mice
(Ocheltree et al., 2005). In addition, the ER of GlySar was 0.54 in wild type
versus 0.94 in Pept2(-/-) mice, suggesting that in Pept2(-/-) mice the renal
reabsorption of GlySar was almost abolished and GlySar was mainly
eliminated by glomerular filtration. By combinatorial usage of wild type and
Pept2 (-/-) mice the relative contribution of Pept1 and Pept2 on the kidney
reabsorption of GlySar was assessed using Equation 6.2. Of the 46% of GlySar
that was reabsorbed in wild type mice, Pept2 accounted for 86% and Pept1
accounted for 14% of the reabsorption.
P-gp is localized at the apical brush-border membrane of the proximal renal
tubule in the kidney that implies its function in renal secretion. Hori et al.
(1993) demonstrated that digoxin was actively secreted in the isolated perfused
rat kidney with the ER of 2.5. P-gp inhibitors, quinidine, and verapamil
decreased the ER of digoxin to unity, suggesting that digoxin is actively
secreted into urine by P-gp. The function of Bcrp1 expressed on the brush-
border membrane of proximal tubule cells of the kidneys in the renal secretion
was first demonstrated by Mizuno et al. The renal clearance of E3040S
(6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole sul-
fate) was 2.4-fold lower in Bcrp1(-/-) mice compared to that in wild type mice
(Mizuno et al., 2004). However, BCRP expression is negligible in the human
kidney (Hori et al., 1993). Given that species differences in renal localization of
BCRP could lead to different routes of elimination of BCRP substrates, one
must take the interspecies differences into consideration when predicting
human PK and route of elimination using preclinical PK data.
BCRP plays an important role in transporting drug into human milk. BCRP
expression is strongly induced in lactating, but not in virgin or nonlactating,
mammary gland epithelia of mice, cows, and humans (Jonker et al., 2005).
Nitrofurantoin, a commonly used urinary tract antibiotic prescribed to
152 DRUG TRANSPORTERS IN DRUG DISPOSITION, DRUG INTERACTIONS