Arch Pharm Res Vol 34, No 11, 1939-1943, 2011
DOI 10.1007/s12272-011-1114-z
1939
Effects of Pluronic F68 and Labrasol on the Intestinal Absorption and
Pharmacokinetics of Rifampicin in Rats
Li Ma
1,2
, Yuhui Wei
2
, Yan Zhou
2
, Xiaohua Ma
1,2
, and Xin'an Wu
2
1
College of Pharmacy, Lanzhou University, Lanzhou 730000, China and
2
Department of Pharmacy, 1st Hospital of Lanzhou
University, Lanzhou 730000, China
(Received January 26, 2011/Revised April 14, 2011/Accepted May 3, 2011)
The aim of this study was to investigate the effects of Pluronic F68 and Labrasol on the intes-
tinal absorption and pharmacokinetics of rifampicin. Intestinal permeability of rifampicin
with or without excipients was evaluated by an
in situ
single-pass perfusion method. A high-
performance liquid chromatographic method was applied to study the pharmacokinetics of
rifampicin with or without excipients. Labrasol or Pluronic F68 (0.1% and 0.05%, v/v), co-per-
fused with rifampicin (60
µ
g/mL), significantly increased
in situ
permeability. Similarly, vera-
pamil (a typical P-gp inhibitor) also increased
in situ
permeability, but to a lesser extent.
In
vivo
, the oral administration of rifampicin with or without Pluronic F68, Labrasol or vera-
pamil resulted in statistically significant effect on t
1/2
(4.83 to 7.75, 6.42 and 7.46 h) and total
body clearance (0.46 to 0.26, 0.28, 0.24 L/h/kg). In addition, Pluronic F68, Labrasol and vera-
pamil produced minor changes in AUC
0-t
, which improved 1.55-, 1.54-, and 1.73-fold in com-
parison to control group, respectively. These results showed that Labrasol and Pluronic F68
might inhibit the function of P-gp in the intestine, thereby increasing intestinal absorption
and changing the pharmacokinetic parameters of rifampicin. Therefore, excipient selection is
an important factor to consider in rational formulation design.
Key words:
Pluronic F68, Labrasol, Rifampicin, P-gp, Intestinal absorption, Pharmacokinetics
INTRODUCTION
Rifampicin is an important anti-tuberculosis drug
with both early bactericidal activity and, more impor-
tantly, sterilizing activity against
Mycobacterium tu-
berculosis
(Mitchison, 1992). The daily dose of rifampi-
cin is 10 mg/kg body weight, and the absolute bioa-
vailability of rifampicin is reported to be 50-68% of this
dose (Koup et al., 1986; Burman et al., 2001; Pandey
et al., 2003). The drug also shows variable absorption.
The maximum concentration (C
max
)
values have been
reported to range from 8 to 24
µ
g/mL in various studies
(Pillai et al., 1999; Pargal and Rani, 2001; Shishoo et
al., 2001). This variability can be attributed to many
factors, such as physicochemical parameters, excipi-
ents, food intake, etc. It is clear that physicochemical
parameters have a significant effect on oral absorption
of rifampicin However, no information is available on
the effects of excipients on the oral absorption of ri-
fampicin.
Surfactants are extensively used to increase the
absorption of drugs from the intestine, as they increase
the solubility of hydrophobic molecules, increase mem-
brane fluidity or disrupt tight junctions, interact with
metabolic enzymes and inhibit efflux transporters
(Nerurkar et al., 1997). In addition, several common
surfactants are reported to affect the absorption of P-
glycoprotein (P-gp) substrates. For instance, Cremophor
EL, Tween 80, Labrasol and Pluronic F68 increased
the absorptive transport of P-gp substrates by inhibit-
ing secretion-directed transport in Caco-2 cells, and
enhanced the intestinal absorption in a rat model
(Rege et al., 2002; Lin et al., 2007; Huang et al., 2008).
Recent studies showed that the absorption of rifam-
picin in the jejunum and the ileum was restricted by a
P-gp-mediated efflux mechanism (Mariappan and
Singh, 2004). Therefore, intestinal absorption of rifam-
Correspondence to:
Xin’an Wu, Department of Pharmacy, 1st
Hospital of Lanzhou University, Lanzhou 730000, China
Tel, Fax: 86-931-861-6392
E-mail: xinanwu6511@163.com