lactating woman was reported to be secreted into human milk (Merino et al.,
2005). The underlying mechanism was demonstrated in mice where milk-
to-plasma ratio of nitrofurantoin in wild type was 80 times higher compared to
that in Bcrp1 knockout mice. Elimination of nitrofurantoin via milk, however,
was somewhat higher than its hepatobiliary elimination (7.5–15% versus 9% of
the dose 1 h after IV injection) in lactating mice. Most of other BCRP
substrates such as PhIP, topotecan, acyclovir, cimetidine, doxorubicin, and
doxorubicinol but not folic acid, DHEAS, or porphyrin vitamin B12
concentrated in the milk and have high milk/plasma ratios (Jonker et al.,
2005). The identification of the BCRP function in mammary gland has
provided insight into the proper usage of BCRP substrate drugs in lactating
woman.
6.2.5 Transporters in Toxicity
Generation of bile flow is regulated by ATP-dependent process and depends on
the coordinated action of a number of transporter proteins in the sinusoidal
and canalicular domains of the hepatocyte. Dysfunction or inhibition of any of
these proteins can lead to retention of substrates or their metabolic products,
with hyperbilirubinemia or cholestasis as a result. Bilirubin, the end product of
heme catabolism, is taken up from blood into hepatocytes by passive diffusion
and the sinusoidal membrane transporter, OATP2, conjugated by UGT in the
hepatocyte and then excreted into the bile through the bile canallicular
membrane transporter, MRP2, mainly as bilirubin glucuronides (Cui et al.,
2001; Muller and Jansen, 1997, Kamisako et al., 2000). Mrp2 deficient rats,
GY/TR(transporter deficient Wistar rats) and EHBR, suffer hyperbilirubi-
nemia and are good models for Dubin–Johnson syndrome, a human disease
which is characterized by hyperbilirubinemia. This syndrome occurs in human
with a hereditary MRP2 deficiency. Since bilirubin–glucuronides are endogen-
ous substrates of MRP2 and excreted from the liver into bile by MRP2
(Gottesman and Ambudkar, 2001), inhibition of MRP2-regulated transport of
bilirubin-glucuronides into the bile can potentially cause hyperbilirubinemia.
Genetical analysis (Ieiri et al., 2004; Huang et al., 2004) and OATP-transfected
cell studies (Campbell et al., 2004) also indicated that lack of OATP or
inhibition of OATP could cause hyperbilirubinemia by the increase of bilirubin
retention.
Pure cholestasis without hepatitis is observed most frequently with
contraceptives and 17a-alkylated androgenic steroids, and the mechanism
most likely involves interference with hepatocyte canalicular efflux systems for
bile salts, organic anions, and phospholipids. The rate-limiting step in bile
formation is considered to be the bile salt export pump (BSEP)-mediated
translocation of bile salts across the canalicular hepatocyte membrane.
Inhibition of BSEP function by metabolites of cyclosporine A, troglitazone,
bosentan, rifampicin, and sex steroids is an important cause of drug induced
cholestasis (Kullak-Ublick, 2004).
ROLES OF TRANSPORTERS IN DRUG DISPOSITION AND TOXICITY 153