Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Transport characteristics of procainamide in the brush-border membrane isolated from rabbit small intestine were studied by a rapid-filtration technique. Procainamide uptake by brush-border membrane vesicles was stimulated by an outward H+ gradient (pHin = 6.0, pHout = 7.5) against a concentration gradient (overshoot phenomenon), and this stimulation was reduced when the H+ gradient was subjected to rapid dissipation by the presence of a protonophore, FCCP. An outward H+ gradient-dependent procainamide uptake was not caused by H+ diffusion potential. The initial uptake of procainamide was inhibited by other tertiary amines with N-dimethyl or N-diethyl moieties in their structures, such as triethylamine, dimethylaminoethyl chloride, and diphenhydramine, but not by tetraethylammonium and thiamine. Furthermore, procainamide uptake was stimulated by preloading the vesicles with these tertiary amines (trans-stimulation effect), indicating the existence of a specific transport system for tertiary amines. These findings indicate that procainamide transport in the intestinal brush-border membrane is mediated by the H+/tertiary amine antiport system that recognizes N-dimethyl or N-diethyl moieties in the structures of tertiary amines.
organic cation; intestinal absorption; intestinal secretion; antiporter
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
COMPARED WITH KIDNEY AND LIVER, there are few data concerning the mechanisms of organic cation transport in the intestine (8, 30). The mechanisms of intestinal absorption of organic cations have mainly been explained by passive diffusion of nonionized compounds according to the pH partition theory. However, other contributions have been described (8, 30); these include membrane potential-dependent transport mechanisms (6, 18, 19, 22, 24) and specific transport systems for choline (7, 20) and thiamine (10). In addition, saturable transport of several cationic drugs has been reported (9, 16, 26, 27). On the other hand, intestinal secretion of organic cations was first demonstrated in isolated guinea pig intestinal mucosa (28, 29). Later studies demonstrated the active secretion of various organic cations into the intestinal lumen (2, 8, 30). P-glycoprotein localized in the intestinal brush-border membrane is involved in the active intestinal secretion of organic cations (4). A guanidine/H+ antiporter was characterized in intestinal brush-border membrane vesicles (12). It was suggested that the guanidine/H+ exchanger functions as an efflux system for organic cations. However, the details of intestinal absorption mechanisms of organic cations were not clear.
Recently, we (14) demonstrated that diphenhydramine, an antihistamine, is transported by the pH-dependent specific transport system in the human intestinal epithelium cell line Caco-2. Diphenhydramine accumulation was temperature dependent, saturable, and decreased at lower extracellular pH. In addition, tetraethylammonium as well as biological amines and/or neurotransmitters such as histamine, serotonin, dopamine, and choline had no effect on diphenhydramine accumulation. More recently, we (13) showed that diphenhydramine is transported by a pH-dependent tertiary amine transport system in Caco-2 cells (13). This tertiary amine transport system could recognize N-dimethyl or N-diethyl moieties in the structures of tertiary amines such as triethylamine, dimethylaminoethyl chloride, diphenhydramine, chlorpheniramine, and procainamide. Moreover, measurement of changes in intracellular pH induced by the addition of tertiary amines excluded the possibility that pH-dependent transport of diphenhydramine is simply explained by nonionic diffusion of nonionized forms. In the present study, we investigated the transport characteristics of procainamide using rabbit intestinal brush-border membrane vesicles to definitively determine the driving force for this tertiary amine specific transport system. Because diphenhydramine is a relatively hydrophobic compound, we used procainamide, another tertiary amine compound with an N-diethyl moiety, as a substrate. Our data provide the first direct evidence indicating the existence of an H+/tertiary amine antiport system in the intestinal brush-border membrane.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Materials.
[14C]guanidine hydrochloride (2.035 GBq/mmol) was
purchased from Moravek Biochemicals (Brea, CA). Procainamide
hydrochloride and valinomycin were obtained from Sigma Chemical (St.
Louis, MO). Diphenhydramine hydrochloride was purchased from Tokyo
Kasei Kogyo (Tokyo, Japan). (±)-Chlorpheniramine maleate, cimetidine, []-dimethylaminoethyl chloride hydrochloride, guanidine
hydrochloride, tetraethylammonium bromide, thiamine hydrochloride, and
triethylamine hydrochloride were obtained from Nacalai Tesque (Kyoto,
Japan). FCCP was purchased from Fluka (Buchs, Switzerland). All other chemicals were of the highest purity available.
Preparation of brush-border membrane vesicles. Brush-border membrane vesicles were isolated from the small intestine of male rabbits (body wt 2.0-2.3 kg) according to the calcium precipitation method described previously (15). Brush-border membrane was suspended in the buffer needed for the transport experiment (experimental buffer). In general, the experimental buffer contained either 100 mM mannitol, 100 mM KCl, and 10 mM HEPES (pH 7.5) or 100 mM mannitol, 100 mM KCl, and 10 mM MES (pH 6.0), and the medium pH was adjusted with KOH. In membrane potential studies, 100 mM KCl was replaced with 100 mM K-gluconate or Na-gluconate.
Transport studies. The uptake of procainamide and [14C]guanidine by brush-border membrane vesicles was measured by a rapid-filtration technique. The reaction was initiated by the addition of 200 µl of buffer containing the substrate to 20 µl of membrane suspension (11.1-29.6 mg protein/ml) at 25°C. At the stated times, the incubation was stopped by diluting the reaction mixture with 1 ml of ice-cold stop solution containing 150 mM KCl and 20 mM HEPES-Tris (pH 7.5). The mixture was poured immediately onto Millipore filters (HAWP, 0.45 µm, 2.5-cm diameter) and washed once with 5 ml of ice-cold stop solution. The procainamide trapped on the Millipore filter was extracted with 300 µl of distilled water. The extracts were diluted twice with 40 mM KH2PO4-methanol (1:1 vol:vol) containing 0.1% sodium octane sulfate and 0.65% HCl, and procainamide concentration was determined by HPLC as described in Analytical methods. The radioactivity of [14C]guanidine on the filter was determined by liquid scintillation counting. In separate experiments, nonspecific adsorption was estimated by the addition of substrate mixture to 1 ml of ice-cold stop solution containing 20 µl of membrane vesicles. This value was subtracted from uptake data for background correction.
Analytical methods.
Procainamide was assayed using an LC-10A high-performance liquid
chromatograph (Shimadzu, Kyoto, Japan) equipped with an SPD-6A ultraviolet spectrophotometric detector (Shimadzu) and an integrator (Chromatopac C-R1A, Shimadzu) under the following conditions: column,
L-column ODS with 4.6-mm inside diameter × 150 mm (Chemicals Inspection and Testing Institute, Tokyo, Japan); mobile phase, 20 mM
KH2PO4-methanol (3:1) containing 0.05% sodium
octane sulfate; flow rate, 0.8 ml/min; wavelength, 254 nm; injection
volume, 50 µl; temperature, 40°C. The detection limit was
~10 pmol. The protein content of the vesicles was determined by the
method of Bradford (3) using a Bio-Rad protein assay kit
(Bio-Rad Laboratories, Richmond, CA) with bovine -globulin as a standard.
Statistical analysis. Data were analyzed statistically by nonpaired t-test or one-way ANOVA followed by Scheffé's test when multiple comparisons were needed. Probability values <5% were considered significant.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Osmotic sensitivity of procainamide uptake.
To ascertain that the uptake of procainamide by brush-border membrane
vesicles represented transport into the intravesicular space rather
than binding to the membrane surface, the uptake of procainamide at 30 min was measured while decreasing the intravesicular space by
increasing the medium osmolarity with mannitol. As shown in Fig.
1, there was a linear relationship
between procainamide uptake and the reciprocal of the medium
osmolarity, suggesting that procainamide entered into an intravesicular
space. Extrapolation of procainamide uptake to infinite osmolarity,
i.e., to zero intravesicular space, suggested that binding comprised
~50% under the incubation conditions in the present study.
|
Effect of H+ gradient on procainamide uptake.
Because transport of tertiary amines such as diphenhydramine and
procainamide is pH dependent, the effect of an H+ gradient
on procainamide uptake by rabbit intestinal brush-border membrane
vesicles was examined. Figure 2 shows the
time course of procainamide uptake in the presence and absence of an
H+ gradient. The initial rate of procainamide uptake was
markedly stimulated in the presence of an outwardly directed
H+ gradient [intravesicular pH (pHin) = 6.0, extravesicular pH (pHout) = 7.5], exhibiting
uphill transport (overshoot phenomenon). In contrast, uptake
was not stimulated in the absence of an H+ gradient
(pHin = pHout = 6.0 or
pHin = pHout = 7.5) or the presence of an inwardly directed H+ gradient (pHin = 7.5, pHout = 6.0). Thus the outward H+
gradient serves as a driving force for the active transport of procainamide in the intestinal brush-border membrane.
|
Effect of FCCP on procainamide uptake.
To further evaluate the effect of an outwardly directed H+
gradient on procainamide uptake, the effect of FCCP, a protonophore, was examined. As shown in Fig. 3, the
initial rate of procainamide uptake in the presence of an
outwardly directed H+ gradient (pHin = 6.0, pHout = 7.5) was markedly reduced in the presence
of FCCP. However, the equilibrium values of procainamide uptake were
similar in the presence and absence of FCCP, indicating that FCCP did
not affect intravesicular volume. To determine whether the effect of
FCCP is nonspecific, the effect of FCCP on procainamide uptake was
examined in the absence of an H+ gradient
(pHin = pHout = 7.5); the results
demonstrate that procainamide uptake in the absence of an
H+ gradient was unaffected by FCCP (Fig. 3).
|
Effect of membrane potential on procainamide uptake.
To determine whether procainamide uptake depends on membrane
potential, the effect of a K+ diffusion potential generated
by valinomycin on procainamide uptake was examined. As shown in Fig.
4, procainamide uptake in the absence of
an H+ gradient was only slightly enhanced by
valinomycin-induced inside negative membrane potential [intravesicular
K+ concentration ([K+]in) = extravesicular Na+ concentration
([Na+]out) = 100 mM]. In addition,
H+ gradient-stimulated procainamide uptake was not altered
by the presence of valinomycin used to voltage-clamp the membrane
vesicles ([K+]in = [K+]out = 100 mM; data not shown). These
results suggest that the interior negative membrane potential does not
affect procainamide uptake to any great extent.
|
Kinetic analysis of procainamide uptake.
The concentration dependence of procainamide uptake was examined in the
presence of an outward H+ gradient. Figure
5 shows the initial uptake of
procainamide as a function of the substrate concentration ranging from
0.5 to 50 mM. Kinetic parameters were calculated using nonlinear
least-squares regression analysis from the following Michaelis-Menten
equation
![]() |
|
Effect of various organic cations on procainamide uptake.
The effect of various organic cations on procainamide uptake by
intestinal brush-border membrane vesicles was examined in the presence
of an outward H+ gradient (pHin = 6.0, pHout = 7.5). As shown in Fig.
6, guanidine and cimetidine slightly but
significantly inhibited the procainamide uptake, whereas
tetraethylammonium and thiamine had no effect. Tertiary amine compounds
with N-dimethyl or N-diethyl moieties in their
structures, such as triethylamine and dimethylaminoethyl chloride,
markedly inhibited procainamide uptake. Furthermore, antihistamines
that contain an N-dimethyl moiety, such as diphenhydramine and chlorpheniramine, also inhibited the procainamide uptake.
|
Trans-stimulation effect on procainamide uptake.
To elucidate whether the procainamide uptake is mediated by a specific
transport system, trans-stimulation effect of various organic cations on procainamide uptake was examined in the absence of
an H+ gradient. As shown in Fig.
7, the initial uptake of procainamide was
stimulated by preloading the vesicles with triethylamine or dimethylaminoethyl chloride. However, neither cimetidine nor guanidine at various concentrations showed a trans-stimulation effect
on procainamide uptake. In addition, [14C]guanidine
uptake by brush-border membrane vesicles was not stimulated by
preloading the vesicles with various concentrations of procainamide (data not shown).
|
Effect of K+ on procainamide and guanidine uptake.
The lack of a trans-stimulation effect of guanidine on
procainamide uptake and vice versa suggested that the
H+/tertiary amine antiport system is different from the
H+/guanidine antiport system. To compare the transport
characteristics of these transport systems, we examined the effect of
medium composition on procainamide and [14C]guanidine
uptake because H+/guanidine antiport is reported to be
inhibited by inorganic monovalent cations (12). As shown
in Fig. 8, [14C]guanidine
uptake was markedly inhibited in the presence of 100 mM K+,
whereas procainamide uptake was not affected. These results suggest
that the H+/tertiary amine antiport system is different
from the H+/guanidine antiport system.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Recently, it has been suggested that luminal excretion (exsorption) of organic cations is an important role of the intestinal epithelia (2). Toxic organic cations such as xenobiotics may be secreted into the lumen to prevent their toxicity. Procainamide, a tertiary amine, is reported to be a substrate for the renal H+/organic cation antiport system (11, 25). Intestinal secretion of procainamide to the lumen was also reported in a study of the luminal perfusion technique used to reduce its blood concentration (1). However, the intestinal transport mechanism of procainamide was not well defined. In a previous report (13), we demonstrated the existence of a pH-dependent tertiary amine specific transport system in Caco-2 cells. This transport system could recognize tertiary amines with N-dimethyl or N-diethyl moieties, such as diphenhydramine and procainamide. In the present study, to definitively determine the driving force for the tertiary amine transport system, we carried out transport studies using isolated intestinal brush-border membrane vesicles. Because diphenhydramine is a relatively hydrophobic compound, we used procainamide, another tertiary amine compound with an N-diethyl moiety, as a substrate.
It was demonstrated that the binding of some lipophilic organic cations to the brush-border membrane or the instruments, such as the filtration filter, resulted in a failure to detect the vesicular uptake of the organic cations (17, 21). Although considerable binding of procainamide was found in the present study, procainamide uptake by intestinal brush-border membrane vesicles showed osmotic sensitivity, indicating that procainamide was taken up into an osmotically responsive space. Osmotic sensitivity of procainamide uptake was also reported in rabbit renal brush-border membrane vesicles (11).
Procainamide uptake was stimulated by an outward H+ gradient, but not by a Na+ gradient, and transient accumulation of procainamide against a concentration gradient was observed (overshoot phenomenon). This stimulated transport was reduced in the presence of FCCP, a protonophore. These findings suggest that procainamide is actively transported and that an outward H+ gradient serves as a driving force for procainamide transport. On the other hand, previous studies have demonstrated that the stimulation of organic cation uptake by an outward H+ gradient in the intestinal brush-border membrane is caused by the generation of an H+ diffusion potential, rather than the H+ gradient itself (6, 22, 24). Miyazaki and colleagues have shown such an H+ diffusion potential-dependent uptake of tryptamine (6, 22) and disopyramide (24) by rat intestinal brush-border membrane vesicles.
The K+ diffusion potential generated by valinomycin slightly influenced the procainamide uptake. The uptake of procainamide by intestinal brush-border membrane vesicles was enhanced by the inside negative membrane potential. It is likely that transport of cationic compounds depends on the transmembrane potential differences. In the present study, however, it was evident that the effect of the K+ diffusion potential on procainamide uptake was much smaller than that of an outward H+ gradient. Sugawara et al. (22) reported that the uptake of tryptamine, an organic cation, was stimulated by an outward H+ gradient. However, this H+ gradient-dependent stimulation of tryptamine uptake was not reduced by FCCP. The uptake was diminished in voltage-clamped membrane vesicles induced by valinomycin. Therefore, it was concluded that tryptamine uptake depends on the H+ diffusion membrane potential. In the present study, however, the outwardly directed H+ gradient-stimulated procainamide uptake was reduced by the presence of FCCP, whereas the uptake was not affected in the presence of valinomycin (voltage-clamped membrane vesicles). Thus the outward H+ gradient, but not H+ diffusion potential, serves as the driving force for procainamide uptake by intestinal brush-border membrane vesicles.
The organic cation/H+ antiport system has been extensively studied in the kidney (5, 8, 30). Tetraethylammonium has been used as a typical substrate, and procainamide was reported to be a substrate (11). In the present study, however, tetraethylammonium had no effect on procainamide uptake by intestinal brush-border membrane vesicles. Therefore, it is likely that the procainamide/H+ antiport system in the intestinal brush-border membrane is different from that in the kidney. The presence of an H+-coupled antiport system in the intestinal brush-border membrane was also demonstrated for guanidine transport (12) and thiamine transport (10). In the present study, thiamine had no inhibitory effect on procainamide uptake. Although guanidine inhibited the procainamide uptake, procainamide uptake was not stimulated by preloading the vesicles with various concentrations of guanidine. This lack of trans-stimulation effect of guanidine on procainamide uptake suggests that the procainamide transport system is different from the H+/guanidine antiport system. In addition, [14C]guanidine uptake was markedly inhibited in the presence of 100 mM K+, whereas procainamide uptake was not affected. Because guanidine uptake by intestinal brush-border membrane vesicles was sensitive to inorganic monovalent cations (12), these results suggest that the H+/tertiary amine antiport system is different from the H+/guanidine antiport system.
Recently, we (13) demonstrated that a pH-dependent tertiary amine transport system is present in human intestinal epithelial Caco-2 cells. This transport system could recognize tertiary amines with N-dimethyl or N-diethyl moieties in their structures. Moreover, measurement of changes in intracellular pH induced by the addition of tertiary amines excluded the possibility that pH-dependent transport of diphenhydramine is simply explained by nonionic diffusion of nonionized forms. In the present study, tertiary amines with N-dimethyl or N-diethyl moieties such as triethylamine and dimethylaminoethyl chloride inhibited the H+ gradient-stimulated procainamide uptake. In addition, preloading the brush-border membrane vesicles with triethylamine and dimethylaminoethyl chloride stimulated the procainamide uptake (trans-stimulation effect).
These cis- and trans-interactions of tertiary amines with procainamide uptake could also be explained by the physical process of nonionic diffusion and ion trapping. Indeed, Takagi et al. (23) reported the pH-dependent transport of weak acids such as salicylic acid across liposomes. They explained these observations simply by the physical process, and the same phenomenon could apply to the transport of weak bases. If procainamide transport is simply mediated by the physical process, cis-inhibition and trans-stimulation effects of tertiary amines on procainamide uptake should be dependent on their membrane permeability to collapse or generate the transmembrane H+ gradient. In this context, the potency of tertiary amines to induce cis-inhibition and trans-stimulation effects on procainamide uptake should be similar. However, the inhibitory effect of dimethylaminoethyl chloride and triethylamine on procainamide uptake was quite similar (Fig. 6), although diethylaminoethyl chloride showed much more trans-stimulatory effect on procainamide uptake than triethylamine did (Fig. 7). Furthermore, in our preliminary experiments, procainamide uptake was trans-inhibited, rather than trans-stimulated, by preloading the membrane vesicles with 10 mM diphenhydramine. Because diphenhydramine was shown to be a potent inhibitor of procainamide uptake (Fig. 6), it seems unlikely that the cis- and trans-interactions of diphenhydramine with procainamide transport are simply explained by nonionic diffusion and ion trapping. Although nonionic diffusion and ion trapping might account for the H+ gradient-dependent procainamide transport to some extent, our findings suggest the existence of a novel H+/tertiary amine antiport system in the intestinal brush-border membrane. Because the luminal pH is more acidic than the intracellular pH, it is likely that the physiological function of this transport system is to secrete these tertiary amines to the luminal side of the intestine.
In conclusion, procainamide is transported by a novel H+/tertiary amine antiport system in the intestinal brush-border membrane. To our knowledge, this is the first report indicating the existence of a tertiary amine specific antiport system driven by an H+ gradient in the intestinal brush-border membrane. This antiport system contributes to the intestinal secretion and/or absorption of tertiary amines such as procainamide.
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan and by a Grant-in-Aid from the Uehara Memorial Foundation.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: K. Inui, Dept. of Pharmacy, Kyoto Univ. Hospital, Sakyo-ku, Kyoto 606-8507, Japan (E-mail: inui{at}kuhp.kyoto-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 20 December 1999; accepted in final form 1 May 2000.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Arimori, K,
Hashimoto Y,
and
Nakano M.
Comparison of transport of procainamide and N-acetylprocainamide from blood into the intestinal lumen with that into the peritoneal cavity in rats.
Chem Pharm Bull (Tokyo)
38:
2050-2052,
1990[ISI][Medline].
2.
Arimori, K,
and
Nakano M.
Drug exsorption from blood into the gastrointestinal tract.
Pharm Res
15:
371-376,
1998[ISI][Medline].
3.
Bradford, MM.
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
Anal Biochem
72:
248-254,
1976[ISI][Medline].
4.
Hsing, S,
Gatmaitan Z,
and
Arias IM.
The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa.
Gastroenterology
102:
879-885,
1992[ISI][Medline].
5.
Inui, K,
and
Okuda M.
Cellular and molecular mechanisms of renal tubular secretion of organic anions and cations.
Clin Exp Nephrol
2:
100-108,
1998.
6.
Iseki, K,
Sugawara M,
Saitoh N,
and
Miyazaki K.
The transport mechanisms of organic cations and their zwitterionic derivatives across rat intestinal brush-border membrane. II. Comparison of the membrane potential effect on the uptake by membrane vesicles.
Biochim Biophys Acta
1152:
9-14,
1993[ISI][Medline].
7.
Kessler, M,
Acuto O,
Storelli C,
Murer H,
Müller M,
and
Semenza G.
A modified procedure for the rapid preparation of efficiently transporting vesicles from small intestinal brush border membranes. Their use in investigating some properties of D-glucose and choline transport systems.
Biochim Biophys Acta
506:
136-154,
1978[ISI][Medline].
8.
Koepsell, H.
Organic cation transporters in intestine, kidney, liver, and brain.
Annu Rev Physiol
60:
243-266,
1998[ISI][Medline].
9.
Kuo, SM,
Whitby BR,
Artursson P,
and
Ziemniak JA.
The contribution of intestinal secretion to the dose-dependent absorption of celiprolol.
Pharm Res
11:
648-653,
1994[ISI][Medline].
10.
Laforenza, U,
Orsenigo MN,
and
Rindi G.
A thiamine/H+ antiport mechanism for thiamine entry into brush border membrane vesicles from rat small intestine.
J Membr Biol
161:
151-161,
1998[ISI][Medline].
11.
McKinney, TD,
and
Kunnemann ME.
Procainamide transport in rabbit renal cortical brush border membrane vesicles.
Am J Physiol Renal Fluid Electrolyte Physiol
249:
F532-F541,
1985[ISI][Medline].
12.
Miyamoto, Y,
Ganapathy V,
and
Leibach FH.
Transport of guanidine in rabbit intestinal brush-border membrane vesicles.
Am J Physiol Gastrointest Liver Physiol
255:
G85-G92,
1988
13.
Mizuuchi, H,
Katsura T,
Ashida K,
Hashimoto Y,
and
Inui K.
Diphenhydramine transport by pH-dependent tertiary amine transport system in Caco-2 cells.
Am J Physiol Gastrointest Liver Physiol
278:
G563-G569,
2000
14.
Mizuuchi, H,
Katsura T,
Saito H,
Hashimoto Y,
and
Inui K.
Transport characteristics of diphenhydramine in human intestinal epithelial Caco-2 cells: contribution of pH-dependent transport system.
J Pharmacol Exp Ther
290:
388-392,
1999
15.
Okano, T,
Inui K,
Maegawa H,
Takano M,
and
Hori R.
H+ coupled uphill transport of aminocephalosporins via the dipeptide transport system in rabbit intestinal brush-border membranes.
J Biol Chem
261:
14130-14134,
1986
16.
Piyapolrungroj, N,
Li C,
Pisoni RL,
and
Fleisher D.
Cimetidine transport in brush-border membrane vesicles from rat small intestine.
J Pharmacol Exp Ther
289:
346-353,
1999
17.
Saitoh, H,
Kawai S,
Iseki K,
Miyazaki K,
and
Arita T.
Binding of organic cations to brush border membrane from rat small intestine.
J Pharm Pharmacol
40:
776-780,
1988[ISI][Medline].
18.
Saitoh, H,
Kawai S,
Iseki K,
Miyazaki K,
and
Arita T.
Transport characteristics of [3H]-chlorpromazine across rat small intestinal brush border membrane.
J Pharm Pharmacol
41:
200-202,
1989[ISI][Medline].
19.
Saitoh, H,
Kawai S,
Miyazaki K,
and
Arita T.
Transport characteristics of propantheline across rat intestinal brush border membrane.
J Pharm Pharmacol
40:
176-180,
1988[ISI][Medline].
20.
Saitoh, H,
Kobayashi M,
Sugawara M,
Iseki K,
and
Miyazaki K.
Carrier-mediated transport system for choline and its related quaternary ammonium compounds on rat intestinal brush-border membrane.
Biochim Biophys Acta
1112:
153-160,
1992[ISI][Medline].
21.
Saitoh, H,
and
Miyazaki K.
Uptake of methylchlorpromazine by brush-border membrane vesicles from rat small intestine.
Biol Pharm Bull
20:
662-666,
1997[ISI][Medline].
22.
Sugawara, M,
Sasaki M,
Iseki K,
and
Miyazaki K.
Membrane-potential-dependent uptake of tryptamine by rat intestinal brush-border membrane vesicles.
Biochim Biophys Acta
1111:
145-150,
1992[ISI][Medline].
23.
Takagi, M,
Taki Y,
Sakane T,
Nadai T,
Sezaki H,
Oku N,
and
Yamashita S.
A new interpretation of salicylic acid transport across the lipid bilayer: implications of pH-dependent but not carrier-mediated absorption from the gastrointestinal tract.
J Pharmacol Exp Ther
285:
1175-1180,
1998
24.
Takahashi, Y,
Itoh T,
Kobayashi M,
Sugawara M,
Saitoh H,
Iseki K,
Miyazaki K,
Miyazaki S,
Takada M,
and
Kawashima Y.
The transport mechanism of an organic cation, disopyramide, by brush-border membranes. Comparison between renal cortex and small intestine of the rat.
J Pharm Pharmacol
45:
419-424,
1993[ISI][Medline].
25.
Takano, M,
Kato M,
Takayama A,
Yasuhara M,
Inui K,
and
Hori R.
Transport of procainamide in a kidney epithelial cell line LLC-PK1.
Biochim Biophys Acta
1108:
133-139,
1992[ISI][Medline].
26.
Tamai, I,
Saheki A,
Saitoh R,
Sai Y,
Yamada I,
and
Tsuji A.
Nonlinear intestinal absorption of 5-hydroxytryptamine receptor antagonist caused by absorptive and secretory transporters.
J Pharmacol Exp Ther
283:
108-115,
1997
27.
Tan, T,
Kuramoto M,
Takahashi T,
Nakamura H,
Nakanishi Y,
Imasato Y,
and
Yoshimura H.
Characteristics of the gastrointestinal absorption of morphine in rats.
Chem Pharm Bull (Tokyo)
37:
168-173,
1989[ISI][Medline].
28.
Turnheim, K,
and
Lauterbach F.
Interaction between intestinal absorption and secretion of monoquaternary ammonium compounds in guinea pigs: a concept for the absorption kinetics of organic cations.
J Pharmacol Exp Ther
212:
418-424,
1980[ISI][Medline].
29.
Turnheim, K,
and
Lauterbach FO.
Absorption and secretion of monoquaternary ammonium compounds by the isolated intestinal mucosa.
Biochem Pharmacol
26:
99-108,
1977[ISI][Medline].
30.
Zhang, L,
Brett CM,
and
Giacomini KM.
Role of organic cation transporters in drug absorption and elimination.
Annu Rev Pharmacol Toxicol
38:
431-460,
1998[ISI][Medline].