OAT-mediated secretion of methotrexate. By using mouse proximal tubule
cells stably expressing human transporters, methotrexate has been demon-
strated to be taken up via hOAT3 and hOAT1 at the basolateral side of the
proximal tubule and effluxed or taken up at the apical side via hOAT4, where
drug interactions occur between methotrexate and NSAIDs, probenecid, and
penicillin G (Takeda et al., 2002).
Tsuruoka et al. recently reported the first case of severe arrhythmia as a
result of the interaction of cetirizine and pilsicainide by competing renal
excretion via P-gp and OCT. A patient with renal insufficiency who was taking
oral pilsicainide was found to have a wide QRS wave with bradycardia 3 days
after taking oral cetirizine. The plasma concentrations of both drugs were
significantly increased during the coadministration. A follow-up pharmacoki-
netic study in healthy volunteers showed that the renal clearance of cetirizine
(20 mg) or pilsicainide (50 mg) was significantly decreased by about two fold
following coadministration of the two drugs.In vitrostudies using Xenopus
oocytes expressing OCT2 and renal cells transfected with P-gp revealed that the
probe substrate transport was inhibited by either cetirizine or pilsicainide.
These data explained that the elevated concentrations of these drugs are due to
drug-drug interaction via either human P-gp or OCT2 in the renal tubular cells
(Tsuruoka et al., 2006).
Cyclosporine increases the systemic exposure of all statins (lovastatin,
simvastatin, pravastatin, cerivastatin, and rosuvastatin), due to drug-drug
interaction (via either CYPs or transporters like P-gp and OATP) in the
liver. Rosuvastatin has been shown to be a substrate for the human liver
transporter OATP2 and BCRP, but not P-gp. It’s metabolic clearance is
low and mainly mediated by CYP2C9. CsA treatment in transplant
recipients increased AUC0–2handCmaxof rosuvastatin (10 mg) by 7.1 and
10.6-fold, respectively, compared with control values, due to CsA inhibition
of OATP2-mediated rosuvastatin hepatic uptake (Simonson et al., 2004).
6.5.4 Food Effect
Drug–food interactions can often be caused by food or drug supplements
such as St. John’s Wort, an herbal medicine for the treatment of depression
in humans. St. John’s Wort products have shown remarkably decreased
plasma exposure/concentration of certain comedicated drugs, such as CsA
(Mai et al., 2000) and digoxin (Johne et al., 1999), which was attributed to
an inducing effect of St. John’s Wort on CYPs and P-gp activity. Potentially
clinically significant drug interactions were observed with St. John’s Wort
(16/24 studies), garlic (2/5 studies),and American ginseng (1 study) (Mills
et al., 2005).
Grapefruit juice at normal volume of 300 mL decreased AUC andCmaxof
fexofenadine (120 mg) to 58% and 53%, respectively, compared with dosing of
corresponding volume of water in the healthy volunteers, and 1200 mL
grapefruit juice reduced these parameters to 36% and 33%, respectively.
TRANSPORTERS IN DRUG–DRUG OR DRUG–FOOD INTERACTIONS 173