INTERPLAY OF DRUG TRANSPORTERS AND ENZYMES ON HEPATIC DRUG PROCESSING - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 710

SMALL
ORGANIC
ANIONS

BULKY ORGANIC
COMPOUNDS

ORGANIC
CATIONS

MONOVALENT
BILE SALTS

OCT1

NTCP

OATP

OAT2 MCT2

Na +

GSH

H +

MRP2

CYP, UGT

MDR1

MDR3

SULT, GST

MRP3
MRP4
MRP6

BSEP

BCRP

FIGURE 23.1. Schematic diagram of transport and metabolism of drugs in the hepatocyte
which shows influx transporters such as OATP, NTCP, OAT2, OCT1, and MCT2 at the si-
nusoidal membrane; efflux transporters such as MRP3, MRP4, and MRP6 at the basolateral
membrane; and canalicular efflux transporters such as Pgp or MDR1, MDR3, MRP2, BSEP,
and BCRP at the canalicular membrane. Enzymes such as CYP, UGT, SULT and GST are
present to mediate intracellular metabolism. (From ref. 84, with permission.)

is taken up by transporters. Within the cell, the drug may be effluxed immediately back
to the blood or eliminated irreversibly by metabolism or secretion into the bile. To
date, blood flow, vascular [plasma protein and red blood cell (RBC)] binding, trans-
porters, and metabolic enzymes are regarded as important determinants that affect
hepatic drug extraction. 2 , 3
Most drug removal activities have been attributed to the cytochrome P450s
(CYPs), UDP-glucuronosyltransferases (UGTs), glutathione S -transferases (GSTs),
and the sulfotransferases (SULTs) in accounting for irreversible loss of drug due to
metabolism. 4 Uptake transporters on the sinusoidal membrane include the OATPs
(organic anion transporting polypeptides), NTCP (sodium-dependent taurocholate-
cotransporting polypeptide), OCTs (organic cation transporters), and MCT2 (mono-
carboxylic acid transporter 2), and the ABC transporters, Pgp (P-glycoprotein or
MDR1, multidrug resistance protein 1), MRP2 (multidrug resistance-associated pro-
tein 2) , BSEP (bile salt export pump), and BCRP (breast cancer resistance protein) on
the canalicular membrane (Figure 23.1). 5 − 9 Moreover, it is recognized that hepatic
uptake transporters may rate-limit metabolism and excretion in the liver. 10 − 12 Zonal
heterogeneities of transporters and metabolic enzymes further modulate drug disposi-
tion in the liver. 13 , 14 For phase II reactions, rate-limiting roles for cosubstrates 15 , 16 in
conjugation reactions have been described. Complicating factors include the intercon-
version or futile cycling between drug and metabolite, as this presence tends to alter the
simple relationships of clearance with respect to transporters, enzymes, and flow. 17 − 22
The hepatic microcirculation consists of the dual perfusion from the portal vein (PV,
75%) and hepatic artery (HA, 25%). The flow pattern to the liver and the micromixing