DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 381

Noninvasive techniques that utilize radionuclide imaging to track the disposition of
xenobiotics in vivo also have been used to study biliary clearance of drugs. Compounds
tagged with a gamma-emitting radionuclide have been administered in vivo and sub-
sequently tracked through the biological system using an external gamma camera to
assess the rate and extent of absorption, distribution, and excretion of a compound.
A novel method recently developed to collect biliary secretions utilizes an oroen-
teric tube with an occlusive balloon. The hepatobiliary imaging agent 99m technetium
(Tc) mebrofenin is employed in this clinical protocol to evaluate the degree of gall-
bladder contraction in response to pharmacological stimulation and to detect any
leakage of bile due to partial occlusion of the intestine. 128 Hendrikse et al. used
the radiopharmaceuticals 99m Tc-HIDA and 99m Tc-MIBI to assess the function of the
hepatic efflux proteins P-glycoprotein, Mrp1, and Mrp2 in vivo. 129 Another imaging
technique, positron emission tomography (PET), uses a PET camera to measure the
concentration and movement of positron emitters in the living body. An excellent ex-
ample of the utility of imaging to evaluate transport protein function was performed
by Lee et al. using [ 11 C]verapamil to evaluate P-glycoprotein function at the blood-
brain barrier in the rhesus monkey. 130 Imaging techniques may emerge as a powerful
tool to elucidate drug disposition and predict drug-transport interactions.
Microscopy is a widely used and inexpensive noninvasive tool to study hepatic
transport. Both fluorescent and confocal microscopes have been used in conjunc-
tion with fluorescent probes or substrates to study the trafficking and localization of
fluorescently tagged proteins. 19 , 66 , 131 , 132
Pharmacokinetic modeling is a useful tool to aid in analyzing and interpreting the
data generated from in vitro and in vivo model systems. Such mathematical approaches
can provide valuable insights regarding the hepatobiliary disposition of a compound,
including the identification of rate-limiting steps and predictions regarding the impact
of potential alterations in hepatobiliary disposition. Data generated in various model
systems, including the isolated perfused liver, sandwich-cultured hepatocytes, and
transfected cell lines, are amenable to pharmacokinetic analyses. 133-136
13.9. INTERPLAY BETWEEN DRUG METABOLISM AND TRANSPORT
The substantial overlap in substrate specificity, along with the shared response to
prototypical inducers between CYP3A4 and Pgp, has been recognized for more than
a decade. 137 − 139 In addition, a thorough screen of various known CYP3A4 inhibitors
demonstrated that most CYP3A4 inhibitors were able to inhibit Pgp, albeit generally
at higher K i values. 140 More important, this has led to various studies supporting the
concept that CYP3A4 and Pgp act in concert to determine intestinal drug absorption
of substrates. 138 , 141 , 142 Indeed, inhibition of intestinal Pgp was shown to enhance
exposure of common substrates to CYP3A4, thereby increasing overall metabolism
during intestinal transepithelial transport across Caco-2 monolayers. Although the
cellular orientation of apical transporters relative to CYP enzymes in the liver differs
from that in the intestine, hepatic interplay between drug metabolism and biliary ex-
cretion also has been demonstrated. For instance, the extent of hepatic metabolism of