Drug Metabolism in Drug Design and Development Basic Concepts and Practice

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study of Japanese cancer patients revealed that those with variant UGT1A1
alleles were at significantly higher risk of severe adverse reactions to irinotecan
(Ando et al., 2005).
Another example is the major metabolite of gemfibrozil, gemfibrozil
glucuronide, which is produced by a conjugation reaction, namely glucur-
onidation of the parent molecule. Gemfibrozil glucuronide was found to be a
mechanism-based inhibitor of CYP2C8. The IC 50 for inhibition of CYP2C8 by
gemfibrozil glucuronide decreased from 24 to 1.8mM after a 30-min incubation
with human liver microsomes (Ogilvie et al., 2006). The drug interaction
between cerivastatin and gemfibrozil was observed clinically, since the
frequency of rhabdomyolysis was much higher when these two drugs were
administered concurrently (Pogson et al., 1999). The mechanism of this drug–
drug interaction remained unexplained for an extended period at least partially
due to the emphasis put on cytochrome P450 enzymes (Shitara et al., 2004).


7.4.1.7 Transporters Transporter-based drug interactions have been
increasingly reported. P–glycoprotein (P–gp), organic anion transporter
(OAT), organic anion transporting polypeptide (OATP), organic cation
transporter (OCT), multidrug resistance-associated proteins (MRP), and breast
cancer resistant protein (BCRP) are among those relatively well studied. These
drug transporters are related to drug bioavailability and cellular uptake, which
impacts drug clearance, adverse drug interactions, and the enzyme induction and
inhibition. For example, the large inter-subject and inter-racial variations in the
potency of rifampin induction of CYP enzymes now are known to be related to
OATP-C uptake modulation, which results in variations in hepatic cellular levels
of rifampin (Tirona et al., 2003). The needs for studies of various transporters in
the new drug development are dependent on individual programs and the
characteristics of drugs being investigated.
P-gp is located in the apical domain of the enterocyte of the lower
gastrointestinal tract (jejunum, duodenum, ileum, and colon), thereby limiting
the absorption of some drug substrates from the gastrointestinal tract. In other
organs such as the liver and kidney, expression of this transporter at the apical
membrane of hepatocytes and kidney proximal tubular cells results in
enhanced excretion of drug substrates into bile and urine, respectively. P-gp
is also an important component in the blood-brain barrier, limiting the CNS
entry of a variety of drug substrates. P-gp is as well found in other tissues
known to have tissue–blood barriers, such as placenta and testis. Therefore, P-
gp plays an important role in the absorption, distribution, metabolism, and
excretion of test drugs. Since P-gp is the most well understood among drug
transporters, it is generally recommended to evaluate whether the new drug is a
substrate, inhibitor, and/or inducer of P-gp during drug development.
In evaluating whether a new drug is a substrate for P-gp, the net flux ratios
across Caco-2 cells or MDR1-overexpressed cell lines are normally determined.
Net flux ratios2 are considered as positive for P-gp involvement and anin
vivodrug interaction study with a P-gp inhibitor may be warranted. A net flux


DRUG–DRUG INTERACTION STUDIES 225

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