given dexamethasone’s wide therapeutic index and the short duration of
coadministration (Kovarik et al., 1998).
6.5.2 Brain Penetration
The high expressions of P-gp and BCRP at the luminal membrane of brain
endothelia cells imply their roles in the blood–brain barrier. The function of P-gp
in human brain penetration has been demonstrated by DDI studies. However,
the impact of other transporters in human brain is not clear yet. Loperamide, a
potent opiate, is used alone as an antidiarrheal drug without CNS effect due to P-
gp restricted entry to the brain. When loperamide (16 mg) was given with
quinidine at a dose of 600 mg in healthy volunteers, it elicited central opioid
effects indicated by respiratory depression. This can be explained by P-gp
inhibition in BBB and gut, resulting in increased brain penetration of loperamide
and increased oral drug exposure (Sadeque et al., 2000a). In 12 human healthy
volunteers, PET imaging studies have demonstrated that after IV infusion the
brain concentration of½^11 Cverapamil (a P-gp substrate) was significantly
increased upon CsA (a potent P-gp inhibitor) coadministration (Sasongko et al.,
2005), suggesting that P-gp limits its substrate, such as verapamil, across BBB in
man. This PET imaging study appears to be the first report to demonstrate the
function of P-gp in the human BBB.
Ivermectin, a neurotoxic compound in animals with low P-gp expressions,
has been safely used in Africa for the prevention and treatment of river
blindness. The lack of neurotoxicity in African might be due to the high P-gp
expression in African population (Ameyaw et al., 2001). Gene analysis showed
a high frequency of the C allele in the African group than British Caucasian,
Portuguese, southwest Asian, Chinese, Filipino, and Saudi populations, which
implies overexpression of P-gp in African population.
6.5.3 Renal Excretion and Hepatic Clearance
Renal excretion is a major elimination route of many antibiotics and antivirals,
which is partially mediated via uptake by OATs into proximal tubular cells.
With coadministration of probenecid, and nonspecific anion transporter
inhibitor, many cephalosporins, including cephazedone, cefazolin, cefradine,
cefoxitin, cefadroxil, exhibited increased peak concentration, half-life, and
exposure due to inhibition of their renal excretion, enhancing the drug therapy
(Brown, 1993). Nonsteroidal anti-inflammatory drugs (NSAIDs) including
diflunisal, ketoprofen, flurbiprofen, indomethacin, naproxen, and ibuprofen
can inhibit hOAT1-mediated transport of adefovir with IC50sof 0.85–8mM,
which are at the clinically relevant concentrations. Therefore, this NSAIDs–
adefovir interaction may reduce or delay the emergence of adefovir
nephrotoxicity (Mulato et al., 2000).
Severe drug-drug interactions are known to occur between methotrexate
and NSAIDs, probenecid, and penicillin G partially due to inhibition of renal
172 DRUG TRANSPORTERS IN DRUG DISPOSITION, DRUG INTERACTIONS