ROLE OF SELECTED ABC DRUG TRANSPORTERS LIKE BREAST CANCER RESISTANCE PROTEIN (BCRP) AND/OR MULTIDRUG RESISTANCE PROTEIN 4 (MRP4) ON PHARMACOKINETICS OF CIPROFLOXACIN IN NORMAL AND RATS WITH INFLAMMATION
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Date
2015-09-18
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PVNR TVU
Abstract
In the present study, role of BCRP and MRP4 inhibitors, chrysin and
dipyridamole on the pharmacokinetics of ciprofloxacin were investigated in normal
and rats with lipopolysaccharide (LPS from Escherichia coli serotype O55:B5) induced
inflammation. Wistar albino rats, weighing about 250-300 g were randomly divided
into eight groups consisting of six in each group. Group I to IV were normal rats
whereas rats in rest of the four groups (V to VIII) were given LPS (5 mg.kg-1, i.p) to
induce inflammation 24 h prior to the administration of drugs used in the experiment.
In group I (control), rats received ciprofloxacin (20 mg.kg-1) alone orally. In Groups II
and III, chrysin (200 mg.kg-1, PO) and dipyridamole (80 mg.kg-1, PO) were coadministered
with ciprofloxacin, respectively, whereas in group IV, both chrysin and
dipyridamole were co-administered together with ciprofloxacin. Similarly, after
induction of the inflammation in rats by LPS, group V received ciprofloxacin alone and
in group VI and VII, chrysin and dipyridamole were co-administered with
ciprofloxacin, respectively whereas in group VIII, both chrysin and dipyridamole were
co-administered together with ciprofloxacin.
Blood samples were collected from retro orbital sinus at predetermined time
intervals prior to and at 0.166, 0.33, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12 and 24 h after
administration of ciprofloxacin. Plasma was separated and stored at -20ºC until
analyzed for ciprofloxacin by HPLC assay. Based on plasma concentrations obtained
for ciprofloxacin, the pharmacokinetic parameters for ciprofloxacin were determined
by non-compartmental methods.
In normal rats, when ciprofloxacin alone was given, peak plasma concentration
(Cmax) obtained was 1.42±0.10 μg.mL-1, whereas the area under plasma drug
concentration versus time curve (AUC0-t), volume of distribution (Vd/F) and total body
clearance (ClB/F) values were 3.25±0.35 μg.h.mL-1, 12.36±0.82 L.kg-1 and 6.32±0.63
L.kg-1.h-1, respectively. It is observed that co-administration of chrysin along with
ciprofloxacin resulted in marked reduction in the Cmax (0.60±0.11 μg.mL-1) and AUC0-t
(1.06±0.13 μg.h.mL-1), and an increase in the volume of distribution (Vd/F,
300.49±48.7 L.kg-1) and clearance (ClB/F, 192.24±20.2 L.kg-1.h-1) of ciprofloxacin. In
group III, co-administration of dipyridamole in rats resulted in shorter elimination
half-life (0.87±0.06 h) and a decrease in the volume of distribution (7.11±0.92 L.kg-1)
of ciprofloxacin. However, upon co-administration of both chrysin and dipyridamole
together with ciprofloxacin in group IV, the values for Cmax (0.82±0.14 μg.mL-1) and
AUC0-t (1.82±0.34 μg.h.mL-1) of ciprofloxacin were decreased, whereas clearance
(ClB/F, 12.24±2.36 L.kg-1.h -1) was significantly increased.
In group V, induction of inflammation with LPS in rats resulted in marked
reductions in the peak plasma concentration (Cmax, 0.53±0.09 μg.mL-1), area under the
curve (AUC0-t, 1.47±0.20 μg.h.mL-1) and an increase in the volume of distribution
(Vd/F, 25.83±4.27 L.kg-1) and clearance (ClB/F, 14.25±2.00 L.kg-1.h -1) of ciprofloxacin
when compared to group I, wherein ciprofloxacin was administered alone in normal
rats. In group VI, co-administration of chrysin with ciprofloxacin in inflamed rats
resulted in prolonged elimination half-life and mean residence time when compared
to Group V, where as in group VII co-administration of dipyridamole resulted in an
increase in the AUC (4.83±0.70 μg.h.mL-1) and a decrease in volume of distribution
(12.82±1.85 L.kg-1) and clearance (4.35±0.70 L.kg-1.h-1) of ciprofloxacin. Further, the
half-life and mean residence time of ciprofloxacin were significantly prolonged
compared to group V. In group VIII, co-administration of both chrysin and
dipyridamole together with ciprofloxacin in inflamed rats, the AUC of ciprofloxacin
was increased significantly, while the half-life and mean residence time were
prolonged compared to group V.
To conclude, co-administration of chrysin significantly reduced the systemic
concentrations of ciprofloxacin in both normal and inflamed rats either by inhibiting
the uptake transporters involved in the absorption of ciprofloxacin or by physicochemical
interactions with ciprofloxacin leading to formation of poorly soluble
xviii
complex in the intestine or a combination of above two factors, whereas coadministration
of dipyridamole increased systemic exposure of ciprofloxacin in
normal as well as inflamed rats probably by interfering with the renal elimination of
ciprofloxacin by blockade of the MRP4 mediated efflux in the proximal renal tubule
cells.
From the pharmacokinetic point of view, results obtained in the present study
suggest that chrysin may not be increasing the concentration of ciprofloxacin in
plasma to help therapeutic outcome in clinical situations whereas, dipyridamole is
likely to increase the plasma concentrations of ciprofloxacin both in normal and
inflammatory conditions which may be of use in actual clinical situations while using
ciprofloxacin.