Drug Metabolism in Drug Design and Development Basic Concepts and Practice

6.2.3 Transporters in Drug Metabolism

It has been recognized that there is a huge overlap of the substrate specificity
and tissue distributions between P-gp and cytochrome P450 (CYP) 3A. Most
of the CYP3A4 inhibitors also inhibit P-gp (Benet et al., 2003). Inducers of
CYP3A4, such as St. John’s Worts (SJW), reserpine, rifampicin, phenobarbital,
and triacetyloleandomycin, can also induce P-gp expression in cells and in man
(Benet et al., 2003). The spatial relationship of P-gp traversing the plasma
membrane and CYP locating on the endoplasmic reticulum inside the cells
suggests that P-gp may cooperatively influence metabolism by controlling the
exposure of a substrate to CYP enzymes. Drug is absorbed into enterocytes,
hepatocytes, and renal tubular cells where it can be metabolized by CYP3A and
subjected to be pumped out of the cells by P-gp as well. This process allows
CYP3A to have repeated access to the drug molecule, resulting in low
bioavailability of CYP3A substrates, less accumulation of parent compound
inside the cells, and more metabolite formation (Benet et al., 2003). By using
CYP3A4-expressing Caco-2 cell monolayers, the P-gp inhibitor LY335979
(zosuquidar trihydrochloride) (0.5 mM, apical), compared with vehicle, in-
creased saquinavir cell content and its metabolite M7 formation rate, but
decreased the intestinal first-pass extraction (Ei) by approximately 50% (Mouly
et al., 2004).
Efflux pumps also help to eliminate the metabolites of drugs from systemic
circulation. For example, most drug glucuronide-conjugates are MRP2 and/or
BCRP substrates (Adachi et al., 2005) while most sulfate conjugates are BCRP
substrates (Adachi et al., 2005; Zamek-Gliszczynski et al., 2005).

6.2.4 Transporters in Drug Excretion

Transporters are involved in biliary and renal excretions that are the two
common routes of drug elimination. In the liver, a drug is first taken up into
hepatocytes, then either secreted back to the systemic circulation or excreted to
the bile in an intact form or as metabolites via Phase I and/or Phase II
enzymes. Given the involvement of transporters in both uptake at the
sinusoidal membrane and efflux at the sinusoidal and canulicular membranes
(Fig. 6.1c), the hepatic clearance can be expressed based on well-stirred model
as the following equation (Shitara et al., 2005; Yamazaki et al., 1996):

CLH;int¼

PSinfluxðCLH;metþCLBiliaryÞ

PSeffluxþðCLH;metþCLBiliaryÞ

ð 6 : 1 Þ

where CLH, int,CLH, met, and CLBiliaryrepresent the overall hepatic intrinsic
clearance, hepatic metabolism clearance, and biliary excretion, respectively.
PSinfluxand PSeffluxare the membrane transport clearance across the sinusoidal
membrane. When PSeffluxis much smaller than CLH, metand CLBiliary(PSefflux
CLH, met+CLBiliary), the overall hepatic clearance will be equal to PSinflux.At

150 DRUG TRANSPORTERS IN DRUG DISPOSITION, DRUG INTERACTIONS