manifold (two to eight fold) and seems to be related to MDR1 genotype
(Lindell et al., 2003). The interindividual variation of P-gp in intestinal
expression resulted in sevenfold range in the oral bioavailability of P-gp
substrate digoxin (Greiner et al., 1999b) and 30% variability of cyclosporine A
plasma concentration (Lown et al., 1997). The different P-gp expression causes
much intersubject variability than intrasubject variability. For example, the
intra and intersubject coefficients of variation for AUC0–inf of orally
administered P-gp substrate tanilolol were 14.0% and 20.4–29.5%, respectively
(Siegmund et al., 2003).
SNPs in drug uptake transporters such as OATP1B1 (OATP2) have been
shown to influence the exposure of HMG-CoA inhibitors and fexofenadine in
healthy volunteers (Niemi et al., 2004, 2005, 2006b). Rifampicin, a potent
inducer of CYP3A4 and a substrate of OATP2, has been demonstratedin vitro
to show that OATP variants affect the uptake of rifampicin. However, a
clinical study in 38 healthy volunteers suggested that OATP2 polymorphism
did not affect the extent of induction of hepatic CYP3A4 by rifampicin (Niemi
et al., 2006a).
The observed inconsistencies between the various drugs tested can be
explained by various potentially confounding factors (Sparreboom et al.,
2003). Numerous environmental factors affecting the phenotypical activity of
drug transporters must be considered, which may include exogenous chemicals,
food constituents, herbal preparations, and/or therapeutic drug use that may
induce or inhibit the function or expression of the protein. Thus, these
nongenetic factors might hide the potential genetic effects. Another explana-
tion for the discrepancies is related to route of drug administration and drug-
specific differences in metabolism and excretion for various substrates of drug
transporters. For instance CsA is a substrate for P-gp and CYP3A4, but
digoxin is only a substrate for P-gp. Rifampicin is not only a substrate for
OATP2 but also for OATP8, which may compensate for reduced uptake of
rifampicin by OATP2 variants (Niemi et al., 2006a). Finally, distribution of
other unidentified variation(s) in the same gene and/or other genes relevant to
drug disposition might be different among the different human populations
studied.
6.5 Transporters in Drug–Drug or Drug–Food Interactions
In humans, the role of transporters in drug absorption has been indirectly
shown by inhibition or induction studies. Transporter-related drug-drug
interactions can occur during gastrointestinal absorption, hepatic excretion, renal
excretion, blood–brain barrier penetration, and others due to the wide tissue
distribution of transporters. Food and formulation effects on P-gp-mediated drug
absorption process are also well studied. Most important P-gp-mediated
drug-drug interactions observed in clinic are listed in Table 6.3.
158 DRUG TRANSPORTERS IN DRUG DISPOSITION, DRUG INTERACTIONS