Biomedical Engineering Reference
In-Depth Information
1
-adrenergic antago-
nist talinolol and erythromycin or verapamil in humans. An increase in oral bioavail-
ability of talinolol after concomitant administration of erythromycin is observed in
humans.
112
In vitro studies showed that talinolol, a drug that is eliminated primarily
via the urine without any significant systemic metabolism, is a Pgp substrate ac-
tively transported across intestinal Caco-2 cells. Verapamil was able to block this
transport.
113
In rats, coadministration of talinolol and verapamil resulted in increased
oral AUC of talinolol.
114
In vivo experiments in humans demonstrated that talinolol
is actively secreted into the small intestine, and the secretion is reduced by the in-
traluminal supply of the Pgp inhibitor verapamil.
115
These findings were not con-
firmed in a clinical study: Coadministration of talinolol with verapamil decreased the
oral bioavailability of talinolol without affecting the renal clearance of the drug in
healthy volunteers. However, the authors attributed this unexpected result to intestinal
metabolism. Therefore, the relatively low dose of verapamil that was administered
may have been insufficient to inhibit Pgp significantly.
113
,
116
,
117
Other clinically relevant drug interactions described in the literature involve the
antimicrobial drug rifampicin, a well-known inducer of intestinal CYP3A4. How-
ever, recent findings indicated that it can also induce Pgp expression. In a clinical
study the oral bioavailability of digoxin in eight healthy volunteers was decreased by
30% during rifampicin therapy.
118
Intestinal biopsies obtained from the same patients
before and after administration of rifampicin showed a significant increase in intesti-
nal Pgp expression after administration of the antimicrobial drug, which correlated
inversely with the oral AUC of digoxin. In addition, pretreatment with rifampicin had
little effect on the AUC and renal clearance of digoxin. These results suggest that
the digoxin-rifampicin interaction occurs primarily at the intestinal level. Chronic
exposure to rifampicin can thus result in Pgp induction.
118
Similar interactions with
rifampicin have been reported for talinolol,
119
fexofenadine,
120
and cyclosporin A.
121
Administration of rifampicin and talinolol to eight healthy male volunteers resulted
in a significant reduction in the AUC after intravenous and oral talinolol and substan-
tially increased expression of duodenal Pgp.
119
Hamman et al.
120
reported reduction of
peak plasma concentration and increased oral clearance of fexofenadine in 20 healthy
volunteers after oral coadministration of rifampicin. The investigators concluded that
this interaction has been caused by induction of intestinal Pgp. However, in view of
the recent findings indicating that fexofenadine is also an inducer of CYP3A4 and that
organic anion-transporting polypeptides (OATPs) are involved in the hepatic uptake
of fexofenadine,
122
it is likely that the interaction is due to a combination of factors.
Hebert et al. reported a reduction in the oral bioavailability of cyclosporin A from
27% to 10% after oral administration of rifampicin to six healthy volunteers.
121
Since
cyclosporin A is a substrate for both CYP3A4 and Pgp, and since rifampicin is an
inducer of both CYP3A4 and Pgp, the interaction is probably due to a combination
of CYP3A4 and Pgp induction.
Finally, clinically relevant drug-drug interactions have been reported between the
over-the-counter antidepressant herbal St John's wort (SJW) and a wide range of
drugs. Chronic administration of SJW together with cyclosporin A has been asso-
ciated with a significant reduction of cyclosporin plasma levels and increased risk
Drug-drug interaction has also been reported between the
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