steady state the hepatic intrinsic clearance of pravastatin, a substrate for OATP2
and MRP2 (Tokui et al., 1999; Yamazaki et al., 1997), was regulated by the
uptake process, followed by rapid metabolism and/or biliary excretion with
minimal efflux to the systemic circulation in rats after infusion. The total hepatic
elimination rate at steady state exhibited Michaelis–Menton saturation with the
drug concentration and the Km and Vmax obtained in rats with different
mathematical models (i.e., well stirred, parallel tube, and dispersion models)
were comparable with the initial uptake velocity measured from in vitro
hepatocytes (Tokui et al., 1999).
Uptaketransporters,suchasOCT1,OAT2,OATPB,OATP2,OATP8,
and NTCP, in the sinusoidal membrane of hepatocytes affect PSinflux. Efflux
transporters affect PSefflux in the sinusoidal membrane (e.g., MRP3) and
CLbiliaryin the canulicular membranes (e.g., P-gp, BCRP, and MRP2). After
IV administration of nitrofurantoin (a BCRP substrate), AUC in Bcrp1(-/-)
mice was almost two-fold higher than in wild type mice (139.2 min^ mg/mL
versus 73.9 min^ mg/mL). Hepatobiliary excretion of nitrofurantoin was
almost abolished in Bcrp1(-/-) mice (9.6% versus 0.2% in wild type and
Bcrp1 knockout mice, respectively) (Merino et al., 2005). The impact of P-gp
on biliary excretion of its substrate was first indicated by canalicular
membrane vesicle studies and isolated perfused rat liver. Mdr1a(-/-) or
Mdr1a/1b(-/-) mice provide more direct evidence to demonstrate the
involvement of P-gp in biliary elimination of its substrates such as digoxin,
doxorubicin, and vinblastine. Mrp2 appears to have a less profound impact
on the intestinal absorption of its substrates than on their biliary excretion. In
order to assess Mrp2-mediated biliary excretion and oral absorption
respectively, wild type Sprague–Dawley (SD) rats and Eisai hyperbilirubi-
nemic Sprague–Dawley rats (EHBR) received an IV infusion or an oral dose
of furosemide, probenecid, or methotrexate (MTX) (Chen et al., 2003b). The
biliary clearance of probenecid and MTX was reduced approximately 40-fold
in EHBR rats as compared to control rats. Biliary clearance of furosemide
was similar in EHBR and control rats. In all cases, no significant difference in
absorption was observed between EHBR and control rats. This study
demonstrated that Mrp2 mediates the biliary excretion of probenecid and
MTX but not furosemide.
Similar to hepatocytes, a drug needs to be taken up through the basolateral
membrane of renal epithial cells before the drug is excreted into urine.
Metabolism may also occur in the kidney. Efflux transporters on the luminal
brush-border membrane can pump an intact drug or its metabolites into the
urine (Fig. 6.1d). Renal excretion of drugs can be described by three processes:
glomerular filtration, renal tubular secretion (basolateral uptake transporters
and apical efflux transporters are involved in this process), and reabsorption
from the renal tubular lumen (apical uptake transporters are involved in this
process). Generally, renal clearance can be expressed by the following equation:
CLR¼ð 1 FRÞðfuGFRþCLsecÞð 6 : 2 ÞROLES OF TRANSPORTERS IN DRUG DISPOSITION AND TOXICITY 151