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At least 19 recordsLinked to original sources

PubMed2000

Determination of trimebutine and desmethyl-trimebutine in human plasma by HPLC.

A simple and sensitive HPLC method has been developed to measure trimebutine (CAS 39133-31-8, maleate: CAS 34140-59-5) and its main metabolite desmethyl-trimebutine in human plasma. The method was validated according to the Washington Consensus Conference on the Validation of Analytical Methods. It involved extraction of the plasma with n-hexane containing 2-pentanol, followed by reversed-phase HPLC using a Partisil ODS2 10 microns column and UV detection at 265 nm. The retention times of the internal standard (procaine), desmethyl-trimebutine and trimebutine were 2.4, 4.3 and 6.5 min, respectively. The standard curves were linear from 20 ng.ml-1 (limit of quantitation) to 5000 ng.ml-1 for both compounds. The coefficient of variation for all the criteria of validation were less than 15%. The extraction recoveries obtained for trimebutine and desmethyl-trimebutine were about 90%. Both compounds were very stable upon storage in plasma. The method was tested by measuring the plasma concentrations following oral administration to humans during a bioequivalence study and was shown suitable for pharmacokinetic studies.

Calibration↗

PubMed2000

Pharmacokinetics and bioequivalence of two trimebutine formulations in healthy volunteers using desmethyl-trimebutine levels.

Trimebutine tablets (dimethylamino-2-phenyl-2-n-butyl-3,4,5- trimethoxybenzoate maleate, CAS 34140-59-5, reference) and a new tablet formulation (Eurogalena, test) were administered in 24 healthy volunteers of both sexes according to a cross-over design, in a single dose of one 100 mg tablet of each formulation. Blood samples were drawn off over a 24-h period, before (time 0) and after each administration at specific intervals. Trimebutine and its main active metabolite, desmethyl-trimebutine, were measured in plasma using a validated HPLC method with UV detection. For both compounds, the sensitivity was 20 ng.ml-1 and the analytical method was proved to be linear for concentrations between 20 ng.ml-1 and 5000 ng.ml-1, with a variability less than 11%. The non-compartmental method was used for pharmacokinetic analysis. The confidence interval approach was used for comparison of the formulations according to the EU guidance note on bioavailability and bioequivalence on Cmax, AUC0-t and AUC0-infinity, log transformed. Tmax values were statistically compared using the Friedman non-parametric test. No trimebutine concentration was measured in the plasma samples. The obtained data with desmethyl-trimebutine proved the bioequivalence of the two tested formulations.

Adult↗

PubMed2004

Beneficial effect of trimebutine and N-monodesmethyl trimebutine on trinitrobenzene sulfonic acid-induced colitis in rats.

The use of local anesthetics, such as lidocaine, has been proposed in the treatment of distal ulcerative colitis. Trimebutine maleate (TMB) displays a local anesthetic activity higher than that of lidocaine in rabbit corneal reflex. TMB and nor-TMB its main metabolite in human show similar affinity to that of bupivacaine toward sodium channel labeled by [3H]batrachotoxin and block sodium currents in sensory neurons from rat dorsal root ganglia. The aim of this study was to evaluate the effects of TMB and nor-TMB in comparison to lidocaine and bupivacaine in a rat model of acute colonic inflammation induced by trinitrobenzene sulfonic acid (TNBS). A single intracolonic instillation of TNBS (50 mg/kg dissolved in ethanol 30%) led to early plasma extravasation then macroscopic damage (hyperemia and necrosis), increased colonic weight and tissular MPO, a marker of neutrophilic infiltration. Local administration of TMB at dose of 3 to 60 mg/kg, 30 min before, 24 and 48 h after colitis induction, significantly reduced the severity of colitis. Nor-TMB (1, 3, 10, 30 mg/kg) as well as lidocaine (1, 3, 10 mg/kg) dose-dependently reduced colitis while bupivacaine at 10 mg/kg did not affect it significantly. In contrast systemic administration of TMB, nor-TMB and lidocaine at 10 mg/kg had no significant effect. Furthermore, local administration of TMB (30 mg/kg) and lidocaine (10 mg/kg) significantly reduced plasmatic extravasation. In conclusion, intracolonic treatment with TMB and nor-TMB improved acute experimental TNBS-induced colitis in rat and these effects could be explained by their local anesthetic activity.

Administration, Rectal↗

PubMed1999

High-performance liquid chromatographic determination of trimebutine and its major metabolite, N-monodesmethyl trimebutine, in rat and human plasma.

A rapid, selective and very sensitive ion-pairing reversed-phase HPLC method was developed for the simultaneous determination of trimebutine (TMB) and its major metabolite, N-monodesmethyltrimebutine (NDTMB), in rat and human plasma. Heptanesulfonate was employed as the ion-pairing agent and verapamil was used as the internal standard. The method involved the extraction with a n-hexane-isopropylalcohol (IPA) mixture (99:1, v/v) followed by back-extraction into 0.1 M hydrochloric acid and evaporation to dryness. HPLC analysis was carried out using a 4-microm particle size, C18-bonded silica column and water-sodium acetate-heptanesulfonate-acetonitrile as the mobile phase and UV detection at 267 nm. The chromatograms showed good resolution and sensitivity and no interference of plasma. The mean recoveries for human plasma were 95.4+/-3.1% for TMB and 89.4+/-4.1% for NDTMB. The detection limits of TMB and its metabolite, NDTMB, in human plasma were 1 and 5 ng/ml, respectively. The calibration curves were linear over the concentration range 10-5000 ng/ml for TMB and 25-25000 ng/ml for NDTMB with correlation coefficients greater than 0.999 and with within-day or between-day coefficients of variation not exceeding 9.4%. This assay procedure was applied to the study of metabolite pharmacokinetics of TMB in rat and the human.

Animals↗

PubMedDate not supplied

Studies of metabolic pathways of trimebutine by simultaneous administration of trimebutine and its deuterium-labeled metabolite.

Trimebutine maleate (I), (+-)-2-dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoate hydrogen maleate, and a deuterium-labeled sample of its hydrolyzed metabolite, 2-dimethylamino-2-phenylbutanol-d3 (II-d3), were simultaneously administered to experimental animals at an oral dose of 10 or 50 mumol/kg, and distribution ratios of the two alternative initial metabolic steps, i.e., ester hydrolysis and N-demethylation, were estimated by determining the composition of the urinary alcohol-moiety metabolites, II, and its mono- and di-demethylated metabolites, III and IV, by GC/MS. In dogs, the order of quantities of the metabolites from II-d3 was II much greater than III much greater than IV, showing predominance of conjugation over N-demethylation. However, this order was reversed when the amounts of the metabolites from I were compared, indicating that I was preferentially metabolized by N-demethylation followed by ester hydrolysis and conjugation in this order. In rats, a considerable proportion of I was presumed to be metabolized by ester hydrolysis before N-demethylation. In in vitro experiments employing the liver microsomes and homogenates of liver and small intestine from rats and dogs, it was found that both ester-hydrolizing and N-demethylating activities were higher in rats than in dogs, and the conjugating activity was higher in dogs than in rats. It was also found that I, having a high lipophilicity, was more susceptible to N-demethylation than less lipophilic II. These results from the in vitro experiments could account for the species differences in the distribution ratio of the metabolic pathways of I in vivo.

Animals↗

PubMed1991

Dual effect of trimebutine on contractility of the guinea pig ileum via the opioid receptors.

Preparations of longitudinal muscle attached to myenteric plexus from guinea pig ileum were used to observe the effect of trimebutine on intestinal motility. Electrical stimulation at 0.2 Hz and 5 Hz produced contraction mediated by the release of acetylcholine in the preparations. The response to low-frequency stimulation (0.2 Hz) was inhibited by trimebutine (10(-8)-10(-5) mol/L), and the response to high-frequency stimulation (5 Hz) was enhanced by the drug at low concentrations (10(-8)-10(-7) mol/L) and inhibited by high concentrations (10(-6)-10(-5) mol/L). This enhancement was mimicked by [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, and was antagonized by naloxone but not by MR2266. Enhancement by trimebutine was inhibited by yohimbine. Trimebutine (greater than or equal to 10(-8) mol/L) inhibited stimulation (5 Hz)-evoked release of norepinephrine, and the trimebutine effect was antagonized by naloxone but not by MR2266. Low concentrations of trimebutine inhibit norepinephrine release via the mu-opioid receptor and enhance intestinal motility by preventing the adrenergic inhibition of acetylcholine release. Inhibition by trimebutine was antagonized either by naloxone or MR2266. High concentrations of trimebutine may inhibit acetylcholine release via the mu- and kappa-opioid receptors, after which the intestinal motility is inhibited. Trimebutine at further high concentrations (greater than 10(-5) mol/L) contracted single smooth muscle cells from the circular muscle layers but not from the longitudinal muscle layers. The usual dose of trimebutine may exert dual effect on the intestinal motility indirectly through cholinergic and adrenergic neurons without direct effect on the smooth muscle.

Acetylcholine↗

PubMed2000

Effects of trimebutine maleate on delayed rectifier K+ currents in guinea-pig ventricular myocytes.

The effects of trimebutine maleate, a drug commonly used to regulate motility in the gastrointestinal tract, on the delayed rectifier K+ current (I(K)) were evaluated in guinea-pig ventricular myocytes to determine whether the drug has a proarrhythmic effect through blockade of I(K). Trimebutine decreased I(K) in a concentration-dependent manner. To investigate the effects of trimebutine on two components of I(K) (I(Kr) and I(Ks); rapidly activated and slowly activated components, respectively), we performed the envelope-of-tails test. Trimebutine-sensitive I(K) was determined by digital subtraction of I(K) during exposure to trimebutine from control I(K) for each duration of the test pulse over the range 50 ms-2 s. The ratio of deltaI(K,tail)/deltaI(K) plotted against pulse duration for trimebutine-sensitive I(K) gradually decreased to a steady-state value as the duration of the test pulse was lengthened. This finding suggested a weak inhibitory effect of trimebutine on both I(Kr) and I(Ks). The effects of trimebutine on the inward rectifier K+ current (I(K1)) responsible for the resting potential and final repolarization phase of the action potential were investigated by applying voltage clamp ramps over a broad range of potentials. No significant effects were observed at 10 or 100 microM. We next investigated the effects of the drug on the L-type Ca2+ current (I(Ca)). Significant inhibition of I(Ca) was observed at trimebutine concentrations greater than 10 microM. These results suggested that trimebutine maleate has weak inhibitory effects on I(Kr), I(Ks) and I(Ca) at concentrations much higher than those in clinical use.

Animals↗

PubMed1993

Effects of trimebutine on colonic function in patients with chronic idiopathic constipation: evidence for the need of a physiologic rather than clinical selection.

A double-blind crossover study on the effects of trimebutine on large bowel function was performed in 24 consecutive patients complaining of chronic idiopathic constipation. Their stool frequency, colonic transit time, and colonic electrical activity were measured. They were divided into a group of constipated patients with "normal" transit time (less than 40 hours) (n = 12) and another group of constipated patients with "delayed" transit time (more than 40 hours) (n = 12). The patients received trimebutine (200 mg/day per os) for one month and a placebo for another month, at random, with a washout period in between. Results show that stool frequency increased (P < 0.001) in all patients as soon as they entered the study; there was no difference between trimebutine and placebo. Colonic transit time was significantly reduced (P < 0.05) with trimebutine in patients with delayed transit time (from 105 +/- 19 hours to 60 +/- 11 hours; mean +/- SE), while it did not change with placebo (from 103 +/- 17 hours to 95 +/- 10 hours). It was slightly but not significantly increased in patients with normal transit time following trimebutine therapy. Electrical activity was not influenced by trimebutine or placebo in constipated patients with normal transit time, either before or after a meal. The number of propagating bursts during the postprandial period was significantly (P < 0.05) increased in patients with delayed transit (from 2.1 +/- 0.3 bursts/hour to 3.5 +/- 0.6 bursts/hour after trimebutine); it was decreased but not significantly with placebo (from 2.6 +/- 0.8 bursts/hour to 1.6 +/- 0.6 bursts/hour) in the same group of patients. Thus, stool frequency in patients with chronic idiopathic constipation was influenced mainly by a placebo effect. Colonic transit time was reduced by trimebutine, but this was found only in patients with delayed colonic transit; myoelectric propagating bursts were increased, and this probably explains the improvement. In conclusion, trimebutine may be of value in the treatment of patients with chronic idiopathic constipation, provided that a careful pathophysiologic evaluation reveals that they have a colonic transit time that exceeds the normal range. In addition, this study provides some argument for selecting patients with functional motor disorders of the large intestine to be entered into a research protocol or to be treated not on the basis of what they complain about--the symptom--but on the basis of some kind of measurement of dysfunction--a corresponding sign.

Action Potentials↗

PubMed1986

Effect of trimebutine on intestinal motility and plasma motilin in the dog.

In a previous report, trimebutine was shown to induce premature periods of phase III activity in fasting dogs, and its action was blocked by naloxone. In this study, we observed that trimebutine (5 mg X kg-1 iv) could induce premature phase IIIs in canine small intestine during interdigestive and digestive periods; trimebutine-induced phase IIIs were migrating along the small intestine faster than spontaneous activity fronts and; trimebutine-induced phase IIIs were accompanied by sharp rises in concentrations of plasma motilin. To further elucidate the trimebutine-stimulatory mechanism, we verified its effects on the release of various circulating peptides that influence intestinal motility: short-interval blood sampling during trimebutine infusion revealed that plasma motilin increases induced by trimebutine preceded the beginning of phase III in proximal duodenum; and gastrin and insulin postprandial releases were abolished by trimebutine. Therefore, trimebutine, by its simultaneous but opposite effects on various peptides that individually carry positive (e.g., motilin) or negative (e.g., gastrin and insulin) influences on the generation of activity fronts, could alter the equilibrium between stimulatory and inhibitory forces in such a way that, in some circumstances (e.g., postprandial period), stimulatory mechanisms become predominant.

Animals↗

PubMed2005

Effect of nor-trimebutine on neuronal activation induced by a noxious stimulus or an acute colonic inflammation in the rat.

Nor-trimebutine is the main metabolite of trimebutine that is used in the treatment of patients with irritable bowel syndrome. Nor-trimebutine has a blocking activity on sodium channels and a potent local anesthetic effect. These properties were used to investigate the effect of nor-trimebutine on spinal neuronal activation induced by models of noxious somato-visceral stimulus and acute colonic inflammation. Nor-trimebutine was administered in rats either subcutaneously 30 min before intraperitoneal administration of acetic acid or intracolonically 30 min before intracolonic infusion of trinitrobenzenesulfonic acid. Abdominal contractions were counted for 1 h as a marker of abdominal pain. c-fos expression was used as a marker of neuronal activation and revealed by immunohistochemistry 1h after intraperitoneal acetic acid injection and 2 h after colonic inflammation. Nor-trimebutine decreased Fos expression in the thoraco-lumbar (peritoneal irritation) and lumbo-sacral (colonic inflammation) spinal cord in laminae I, IIo V, VII and X. This effect was also observed in the sacral parasympathetic nucleus after colonic inflammation. Nor-trimebutine induced a significant decrease of abdominal contractions following intraperitoneal acetic acid injection. These data may explain the effectiveness of trimebutine in the therapy of abdominal pain in the irritable bowel syndrome.

Abdominal Pain↗

PubMed2000

Antinociceptive effect of (S)-N-desmethyl trimebutine against a mechanical stimulus in a rat model of peripheral neuropathy.

Trimebutine (2-dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoate, hydrogen maleate) relieves abdominal pain in humans. In the present study, the antinociceptive action of systemic (S)-N-desmethyl trimebutine, a stereoisomer of N-monodesmethyl trimebutine, the main metabolite of trimebutine in humans, was studied in a rat model of neuropathic pain produced by chronic constriction injury to the sciatic nerve. Mechanical (vocalization threshold to hindpaw pressure) stimulus was used. Experiments were performed two weeks after surgery when the pain-related behaviour has fully developed. (S)-N-desmethyl trimebutine (1, 3, 10 mg/kg s.c.) produced dose-dependent antinociceptive effects on the nerve-injured and the contralateral hindpaw. The effect of the lowest dose (1 mg/kg s.c.) of (S)-N-desmethyl trimebutine on the nerve-injured paw was equal to that seen after a ten time stronger dose on the contralateral paw. The effect of (S)-N-desmethyl trimebutine (1 mg/kg) was not naloxone reversible. The results suggest that systemic (S)-N-desmethyl trimebutine may be useful in the treatment of some aspects of neuropathic pain.

Analgesics↗

PubMed1998

Influence of trimebutine on inflammation- and stress-induced hyperalgesia to rectal distension in rats.

The effects of trimebutine and its major metabolite, N-desmethyltrimebutine on inflammation- and stress-induced rectal hyperalgesia have been evaluated in rats fitted with electrodes implanted in the longitudinal striated muscle of the abdomen. Intermittent rectal distension was performed before and 3 days after induction of rectal inflammation by local infusion of trinitrobenzenesulphonic acid (in ethanol). Stress consisted of 2h partial restraint and rectal distension was performed before and 30min after the end of the partial restraint session. The animals were treated intraperitoneally with trimebutine or desmethyltrimebutine (5, 10 or 20mgkg(-1)) or vehicle 15min before rectal distension. Naloxone (1mgkg(-1)) or saline was injected subcutaneously before trimebutine and desmethyltrimebutine. Before treatment trimebutine at the highest dose (20mgkg(-1)) reduced the abdominal response to rectal distension for the highest volume of distension (1.6mL) whereas desmethyltrimebutine was inactive. After rectocolitis the abdominal response to rectal distension was enhanced and trimebutine at 5mgkg(-1) reduced and at 10 mgkg(-1) suppressed inflammation-induced hyperalgesia, an effect reversed by naloxone. Desmethyltrimebutine was inactive. Stress-induced hypersensitivity was attenuated or suppressed, or both, by trimebutine and desmethyltrimebutine at doses of 5, 10 or 20mgkg(-l); greater efficacy was observed for desmethyltrimebutine and the effects were not reversed by naloxone. It was concluded that trimebutine and desmethyltrimebutine are active against inflammation- and stress-induced rectal hyperalgesia but act differently. The effect of trimebutine on inflammation-induced hyperalgesia is mediated through opioid receptors.

Animals↗

PubMed1991

Effects of trimebutine on cytosolic Ca2+ and force transitions in intestinal smooth muscle.

The effects of trimebutine maleate on cytosolic free Ca2+ and force transitions in the guinea-pig taenia cecum were studied by fura-2 fluorometry and tension recording. The addition of 80 mM K+ induced a transient increase in cytosolic free Ca2+ concentration ([Ca2+]i) and tension, followed by a sustained increase. Trimebutine (10 microM) suppressed both [Ca2+]i elevation and tension development. The tonic responses were more potently inhibited than the phasic responses. Phasic components gradually increased as the added K+ increased (10-40 mM). The relationship between the peak increases in [Ca2+]i and tension was not affected by trimebutine (10 microM). This means that trimebutine does not affect the Ca2+ sensitivity of contractile elements. In a high K+ and Ca(2+)-free medium, carbachol (10 microM) or caffeine (30 mM) caused transient [Ca2+]i elevation and tension development in the smooth muscle. Trimebutine (10 microM) decreased the amplitude of both responses. Trimebutine (10 microM) inhibited the spontaneous fluctuations in [Ca2+]i and motility of taenia cecum in the presence of tetrodotoxin (TTX; 0.3 microM). These results suggest that trimebutine has two types of inhibitory actions on intestinal smooth muscle; one, the inhibition of Ca2+ influx through voltage-dependent calcium channels, and the other, the inhibition of Ca2+ release from intracellular storage sites.

Animals↗

PubMed1993

Effect of trimebutine on voltage-activated calcium current in rabbit ileal smooth muscle cells.

1. The effect of trimebutine on the voltage-dependent inward Ca2+ current was investigated by the whole-cell voltage-clamp technique in single smooth muscle cells from rabbit ileum. 2. Trimebutine (3-100 microM) reduced the Ca2+ current in a concentration-dependent manner. The inhibitory effect on the Ca2+ current was also dependent on the holding potential. The Ca2+ current after a low holding potential was inhibited to a greater extent than that after a high membrane potential: the IC50 values were 7 microM and 36 microM at holding potentials of -40 mV and -60 mV, respectively. The Ca2+ current elicited from a holding potential of -80 mV could not be reduced by as much as 50% of the control by trimebutine at concentrations as high as 100 microM. 3. Trimebutine (30 microM) shifted the voltage-dependent inactivation curve for the Ca2+ current by 18 mV in the negative direction. The affinity of the drug for Ca2+ channels was calculated to be 36 times higher in the inactivated state than in the closed-available state. 4. Blockade of the Ca2+ current by trimebutine, unlike verapamil, was not use-dependent. 5. The results suggest that trimebutine inhibits the voltage-dependent inward Ca2+ current through a preferential binding to Ca2+ channels in the inactivated state in the smooth muscle cell from rabbit ileum. The inhibitory effect of trimebutine on gastrointestinal motility is discussed in the light of the present findings.

Action Potentials↗

PubMed1992

[Effects of trimebutine on colonic propulsion in mice].

Effects of oral administration of trimebutine on colonic propulsion in conscious mice were studied by measuring the time required to evacuate a bead which had been inserted into the colon, and compared with those of metoclopramide and domperidone. In normal animals, trimebutine (10 and 50 mg/kg), metoclopramide (50 mg/kg) and domperidone (50 mg/kg) had no effect on the bead evacuation. Metoclopramide and domperidone at 30 mg/kg showed no effect on the delay of colonic propulsion induced by clonidine, while trimebutine (10 and 30 mg/kg) restored the delay significantly. Trimebutine also showed restoration of the delay induced by loperamide. On the acceleration of the propulsion induced by neostigmine, trimebutine (10 and 30 mg/kg) showed an inhibition. In addition, trimebutine (3-30 mg/kg) dose-dependently suppressed the development of soft feces and/or diarrhea induced by neostigmine. According to the results, it is concluded that trimebutine produces both acceleration and inhibition on the colonic propulsion in mice.

Administration, Oral↗

PubMed1987

Induction of phase 3 of the migrating motor complex in human small intestine by trimebutine.

The effects of trimebutine, a drug used in the treatment of various gastrointestinal motility disorders, have been investigated fed and fasted healthy subjects. Duodenojejunal motility was recorded manometrically with a 4-lumen probe. Trimebutine 50 or 100 mg was injected i.v. 3 or 25 min after observing a spontaneous Phase 3 complex in the fasted state. Other experiments were done in the postprandial state and after intravenous naloxone 0.8 mg. In the fasted state, trimebutine 100 mg, injected 25 min after a spontaneous Phase 3 complex consistently induced a premature Phase 3 complex. The mean duration of the migrating motor complex cycle decreased from 86.4 +/- 10.8 min to 32.5 +/- 1.0 min. Trimebutine 50 mg injected 3 and 25 min after a spontaneous Phase 3 complex did not significantly modify the periodicity of the migrating motor complex. Trimebutine 100 mg initiated Phase 3-like activity in the post-prandial state. Previous intravenous administration of naloxone 0.8 mg (Narcan) suppressed the stimulatory action of TMB. Thus, trimebutine is able to modify the motility pattern in the small intestine of man, possibly by acting at opioid receptors.

Adult↗

PubMed1993

Effect of trimebutine on K+ current in rabbit ileal smooth muscle cells.

The effect of trimebutine on the K+ current in rabbit ileal smooth muscle cells was investigated using the whole-cell patch-clamp technique. Trimebutine (10 microM) inhibited an outward current consisting of a Ca(2+)-dependent K+ current (IKCa) and Ca(2+)-independent K+ current (IKv), elicited by stepping from -80 to -20 mV or more positive. Trimebutine reduced dose dependently the IKv amplitude with an IC50 of 7.6 microM and IKCa amplitude with an IC50 of 23.5 microM. The IKv inhibition was neither voltage- nor use-dependent. Trimebutine (1-100 microM) decreased the amplitude and discharge rate of spontaneous transient outward currents. Trimebutine (30 microM) produced a sustained membrane depolarization of about 10 mV accompanied by a decrease in membrane conductance. The results suggest that the excitatory effects of trimebutine on the gastrointestinal tract may be attributable to the inhibitory action on the K+ current.

Animals↗

PubMed1990

Allosteric interaction of trimebutine maleate with dihydropyridine binding sites.

The effects of trimebutine maleate on [3H]nitrendipine binding to guinea-pig ileal smooth muscle membranes and Ca2(+)-induced contraction of the taenia cecum were studied. Specific binding of [3H]nitrendipine to smooth muscle membranes was saturable, with a KD value and maximum number of binding sites (Bmax) of 0.16 nM and 1070 fmol/mg protein, respectively. Trimebutine inhibited [3H]nitrendipine binding in a concentration-dependent manner with a Ki value of 9.3 microM. In the presence of trimebutine (10 microM), Scatchard analysis indicated a competitive-like inhibition with a decrease in the binding affinity (0.31 nM) without a change in Bmax (1059 fmol/mg protein). However, a dissociation experiment using trimebutine (10 or 100 microM) showed that the decreased affinity was due to an increase of the dissociation rate constant of [3H]nitrendipine binding to the membrane. In mechanical experiments using the taenia cecum, trimebutine (3-30 microM) caused a parallel rightward shift of the dose-response curve for the contractile response to a higher concentration range of Ca2+ under high-K+ conditions in a noncompetitive manner. These results suggest that trimebutine has negative allosteric interactions with 1,4-dihydropyridine binding sites on voltage-dependent Ca2+ channels and antagonizes Ca2+ influx, consequently inhibiting contractions of intestinal smooth muscle.

Animals↗